Improving precision health approaches through large-scale EHRs and biobanks

通过大规模电子病历和生物库改善精准健康方法

• 批准号: 10920219
• 负责人: Joshua Denny
• 金额: $ 140.94万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10920219
• 关键词: Acceleration; Adult; African American; African ancestry; All of Us Research Program; American; Antibiotics; Antihypertensive Agents; BRCA2 gene; Black race; Blood Platelets; Blood Pressure; Bupropion; COVID-19; COVID-19 morbidity; COVID-19 mortality; COVID-19 patient; CYP2C19 gene; Cardiac; Cardiovascular system; Caring; Case/Control Studies; Classification; Clinical; Clinics and Hospitals; Code; Complex; Confidence Intervals; Coronary; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA; Data; Data Set; Development; Diagnosis; Disease; Effectiveness; Electronic Health Record; Environment; Epidemiology; Escitalopram; Ethnic Origin; European; European ancestry; Event; Fracture; Frequencies; Future; Genes; Genetic; Genetic Determinism; Genome; Goals; Graves' Disease; Guidelines; Health; Health Surveys; Heritability; Heterozygote; High Prevalence; Hispanic; Homozygote; Hypertension; Hyponatremia; Hypothyroidism; Iatrogenesis; Inappropriate ADH Syndrome; Individual; Investigation; Laboratories; Life Style; Manuscripts; Measurement; Measures; Medicine; Mendelian randomization; Meta-Analysis; Methods; Morbidity - disease rate; Myocardial Infarction; Nature; Neurologic; Not Hispanic or Latino; Paper; Participant; Pathogenicity; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Population; Population Heterogeneity; Precision Health; Procedures; Provider; Publications; Publishing; Race; Records; Recurrence; Report (document); Reporting; Research; Research Design; Resources; Risk; Sample Size; Sampling; Science; Site; Smoking Status; Source; Symptoms; TSC2 gene; Testing; Uterine Fibroids; Variant; Work; acute drug induced liver toxicity; alpha 1-Antitrypsin Deficiency; ancestry analysis; autosome; biobank; blood pressure elevation; clinically actionable; clopidogrel; cohort; coronavirus disease; cost effective; data format; design; disease diagnosis; drug discovery; drug efficacy; drug induced liver injury; drug repurposing; duloxetine; endometriosis; falls; genetic analysis; genetic architecture; genetic variant; genome sequencing; genome wide association study; genomic locus; genomic predictors; hazard; health disparity; health record; high risk; human disease; improved; individual variation; meetings; multimodality; novel; observational cohort study; personalized medicine; phenome; phenotypic data; phenotyping algorithm; polygenic risk score; precision medicine; programs; rare variant; recruit; response; sex; therapeutic target; tool; trait; translational study; venlafaxine; whole genome

During the current reporting period we have focused on these major projects: 1. PheWAS Studies The All of Us Research Program (All of Us) is a multi-site, national study with the goal of recruiting at least one million participants to further precision medicine. To evaluate how well All of Us data replicated known epidemiological associations, we performed a PheWAS using both EHR and survey-defined smoking status as a well-studied health exposure. For both exposure measures, we replicated most matched-phenotype association effects in published meta-analyses, with 73 phenotypes replicated and 59 replicated with effect sizes whose confidence intervals overlapped. This work was recently accepted for publication in JAMIA. Variation in outcomes for patients infected with COVID-19 is still poorly understood. We conducted a PheWAS to find common phenotypes associated with COVID-19 in the National COVID Cohort Collaborative (N3C) enclave, which is collected as a case and control design based on COVID-19 status and compared these results with a PheWAS in All of Us. We found highly significant findings from PheWAS analyses to be symptoms most notably associated with COVID-19 morbidity and mortality. A manuscript is in development. 2. Study of blood pressure (BP) and hypertension in large-scale biobanks Nearly half of adults in the US have hypertension. We examined the genetic determinants of BP traits in European-ancestry cohorts in a combined analysis of over 1 million individuals. This study yielded >2,100 independent genetic loci, including 113 novel associations, which explain 40% of the heritability in BP levels. A polygenic risk score (PRS) generated from these data revealed clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.514.2 mm Hg, p=9.08e-73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P=9.71e-33) between top and bottom deciles in an independent dataset. The PRS generated from our European meta-analysis was associated with increasing BP in an African-American ancestry sample (N=21,843) from the All of Us cohort: e.g. with sex-adjusted differences between top and bottom deciles of the PRS distribution of 5.4 mm Hg for SBP (95% CI 4.2 to 6.6 mm Hg, p=1.15e-19) and increased sex-adjusted odds of hypertension (OR 1.52; 95% CI 1.3 to 1.78; p=8.11e-8). Taken together, these data demonstrate the utility of conducting both trans-ancestry and ancestry-specific analyses to understand the genetic architecture of complex human disease which may lead to robust therapeutic targets. This work is currently in revision at Nature Genetics. 3. Evaluating drug efficacy in EHR data We used EHR records in All of Us to identify differences in anti-hypertensive drug effectiveness by self-identified race and ethnicity by developing a simple generalizable method to evaluate drug-response effects in EHR data relying on OMOP-formatted data. We used a self-controlled case study design to determine medication effectiveness by calculating the reduction in SBP measurements after medication start. We analyzed 19 commonly used anti-hypertensive medications in 7,465 All of Us participants. Black and Hispanic participants were started on anti-hypertensive medications at higher SBP than White participants. Seven out of 19 anti-hypertensive drugs were less effective in Black and six were less effective in Hispanic, compared to non-Hispanic White participants. A manuscript is in development. 4. Drug effect studies in All of Us We are performing drug-effect studies in drug-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH), idiosyncratic drug-induced liver injury (DILI), and clopidogrel-associated adverse cardiac events in All of Us. SIADH can be caused by a number of medications and is associated with iatrogenic morbidity (e.g., hyponatremia, neurologic complications, falls and fractures). We quantified this risk by performing an observational cohort study in All of Us with some common medications associated with SIADH. We found that duloxetine, venlafaxine, and escitalopram were associated with the highest long-term risk of hyponatremia, and bupropion was associated with the lowest risk. Antibiotics are a known cause of idiosyncratic drug-induced liver injury (DILI). This year, we published a study showing quantified frequency of acute DILI for common antibiotics in All of Us using a validated phenotyping algorithm. Our final case counts were similar to other published results, demonstrating value of All of Us. We intend to study genomic predictors in the future. Antiplatelet therapy with clopidogrel is effective at reducing subsequent events in patients with a recent myocardial infarction (MI) or percutaneous coronary procedure, but its efficacy is influenced by CYP2C19 variants. As a first test of the ability to study pharmacogenomic interactions in All of Us, we evaluated the association of CYP2C19 variants with clopidogrel response in 1,937 participants meeting study definition. As expected, CYP2C19*2 was associated with a higher risk of recurrent cardiovascular events in trans-ancestry analysis (hazard ratio (HR): 1.53, 95% CI: 1.43-1.63, P=6.6e-38). Further analysis is ongoing. 5. Other GWAS in All of Us With the release of whole genome sequencing data for nearly 250,000 All of Us participants this past April, we have launched several genome-wide association in primary hypothyroidism (PH), Graves disease, endometriosis, and uterine fibroids, among others. We have significant findings in PH, Graves, and uterine fibroids. Importantly, these analyses include diverse populations. Our findings for PH, Graves, and uterine fibroids are also being combined with other data sets in larger consortia. 6. Phenotype Risk Scores (PheRS) We have previously demonstrated PheRS as a scalable approach to determine pathogenicity of rare variants in VUMC data (Bastarache, Science 2018). Using genome sequencing data from 81,054 participants with EHR data in All of, we annotated all variants in the 78 genes with clinically actionable phenotypes in the ACMG 3.1 list. We classified these variants according to the ACMG variant interpretation guidelines and identified 6,736 individuals harboring P/LP variants (homozygotes and compound heterozygotes if applicable for autosomal recessive disorder-related genes and heterozygotes for autosomal dominant disorder-related genes) for 69 genes (ACMG positive). PheRS were significantly elevated in ACMG positive individuals for 12 diseases (P< 0.0007). We noted a higher prevalence of ACMG positive individuals for 15 genes among African ancestry individuals and 10 for admixed American ancestry individuals, including BRCA2, TSC2, and HNF1A. We also explored the potential of PheRS as a tool that could aid clinicians to accelerate the diagnosis of Cystic Fibrosis (CF) if implemented as decision support. We analyzed the health records of 965,626 individuals with ongoing care at VUMC. Among the 400 subjects with the highest PheRS for CF, 62% had already been diagnosed with CF. For 26 undiagnosed individuals who had DNA available, we conducted further clinical review and sequencing analysis of CFTR and SERPINA1. This led to the potential diagnosis of two individuals, one with CF and another with alpha-1-antitrypsin deficiency. Moreover, we discovered that six individuals had pathogenic variants (two in CFTR and four in SERPINA1), a more than three-fold enrichment for P/LP variants compared to expected. This paper was recently published in Genetics in Medicine.

在当前的报告期内，我们专注于这些主要项目： 1。Phewas研究 我们所有的研究计划（我们所有人）都是一项多站点的国家研究，其目的是招募至少一百万参与者进一步精确医学。为了评估我们所有人的数据如何复制已知的流行病学关联，我们使用EHR和调查定义的吸烟状况进行了PHEWAS，作为研究良好的健康暴露。对于两种暴露措施，我们在已发表的荟萃分析中复制了最匹配的表型关联效应，并复制了73种表型，并复制了59个，其置信区间重叠的效果大小。这项工作最近被接受在贾米亚（Jamia）出版。 感染COVID-19的患者结局的变化仍然很少了解。我们进行了PHEWAS，以在国家Covid队列协作（N3C）Enclave中找到与COVID-19相关的常见表型，该表型基于COVID-19的状态作为案例和控制设计，并将这些结果与我们所有人的Phewas进行了比较。我们发现，来自Phewas分析的高度显着发现是与19岁的发病率和死亡率有关的症状。手稿正在开发中。 2。大规模生物库中血压（BP）和高血压的研究 美国近一半的成年人患有高血压。我们在对超过100万个人的综合分析中检查了欧洲官员同类中BP特征的遗传决定因素。这项研究产生了> 2,100个独立的遗传基因座，其中包括113个新型关联，这解释了BP水平的40％的遗传力。 A polygenic risk score (PRS) generated from these data revealed clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.514.2 mm Hg, p=9.08e-73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P=9.71e-33) between top and bottom deciles in an independent dataset.我们欧洲荟萃分析产生的PR与我们所有人同类的非裔美国人血统样本（n = 21,843）中的BP增加有关：例如SBP（95％CI 4.2至6.6毫米Hg，p = 1.15e-19）的PRS分布的顶部和底部分解率之间有性别调整的差异，高血压的性别调整几率增加（OR 1.52; 95％CI 1.3至1.78; P = 8.11e-8）。综上所述，这些数据证明了进行跨务疾病和特定于祖先的分析的实用性，以了解复杂人类疾病的遗传结构，这可能导致强大的治疗靶标。这项工作目前正在自然遗传学上进行修订。 3。评估EHR数据中的药物疗效 我们使用了我们所有人中的EHR记录来通过开发一种简单的可推广方法来评估依靠OMOP形式的数据来评估EHR数据中的药物反应效应，从而确定抗高血压药物有效性的差异。我们使用自我控制的案例研究设计来确定药物效率，通过计算药物开始后SBP测量的降低。我们分析了7,465名参与者的19种常用抗高血压药物。 Black和西班牙裔参与者的SBP的抗高血压药物比白人参与者更高。与非西班牙裔白人参与者相比，在19种抗高血压药物中，有7种在黑色中的效果较低，而6种在西班牙裔中的有效性较低。手稿正在开发中。 4。我们所有人的药物效应研究 我们正在对药物诱导的综合征进行药物效应研究，该综合征的不适当抗利尿激素分泌（SIADH），特质性药物诱导的肝损伤（DILI）和与氯吡格雷相关的不良心脏事件。 SIADH可能是由多种药物引起的，并且与医源性发病率有关（例如低钠血症，神经系统并发症，跌倒和骨折）。我们通过在我们所有人中使用与SIADH相关的一些常见药物进行观察队列研究来量化这种风险。我们发现，杜洛西汀，文拉法辛和依他普兰与低钠血症的长期风险最高有关，而安非他酮与最低风险有关。 抗生素是特质药物诱导的肝损伤（DILI）的已知原因。今年，我们发表了一项研究，该研究显示了使用经过验证的表型算法在我们所有人中，急性DILI的量化频率。我们的最终案例计数与其他已发表的结果相似，证明了我们所有人的价值。我们打算在未来研究基因组预测因子。 用氯吡格雷进行抗血小板治疗可有效减少最近心肌梗塞（MI）或经皮冠状动脉程序的患者的随后事件，但其疗效受CYP2C19变体的影响。作为研究我们所有人中药物基因组相互作用的能力的首次测试，我们评估了1,937名参与者符合研究定义的CYP2C19变体与氯吡格雷反应的关联。如预期的那样，CYP2C19*2在跨疗法分析中复发性心血管事件的风险较高（危险比（HR）：1.53，95％CI：1.43-1.63，p = 6.6e-38）。进一步分析正在进行中。 5。我们所有人的其他GWA 随着去年4月，我们近25万名参与者的整个基因组测序数据释放，我们已经在原发性甲状腺功能减退症（PH），Graves病，子宫内膜异位和子宫肌瘤等方面启动了几个全基因组关联。我们在pH，坟墓和子宫肌瘤方面有显着的发现。重要的是，这些分析包括不同的人群。我们对pH，坟墓和子宫肌瘤的发现也与较大的联盟中的其他数据集结合在一起。 6。表型风险评分（pher） 我们以前已经证明了phors作为确定VUMC数据中稀有变体的致病性的可扩展方法（Bastarache，Science 2018）。使用来自所有所有EHR数据的81,054名参与者的基因组测序数据，我们注释了78个基因中的所有变体，具有ACMG 3.1列表中临床可行的表型。我们根据ACMG变体解释指南对这些变体进行了分类，并确定了6,736个携带P/LP变体的个体（如果适用于常染色体膜片相关的基因，纯合子和化合物杂合子，则适用于69型基因的常染色体占主导型基因）（ACMG）基因（ACMG）。对于12种疾病，ACMG阳性个体的pHOR显着升高（P <0.0007）。我们注意到，非洲血统个体中15个基因的ACMG阳性个体的患病率较高，其中包括BRCA2，TSC2和HNF1A在内的混合式美国血统个体的患病率更高。 我们还探讨了phers作为一种工具的潜力，该工具可以帮助临床医生（如果以决策支持为支持）加速囊性纤维化（CF）的诊断。我们分析了VUMC持续护理的965,626个人的健康记录。在CF球员最高的400名受试者中，已经被诊断出患有CF。对于26个未诊断的DNA的人，我们对CFTR和SERPINA1进行了进一步的临床审查和测序分析。这导致了两个人的潜在诊断，一个人患有CF，另一个患有α-1-抗抗蛋白酶缺乏症。此外，我们发现六个人具有致病性变异（CFTR中的两个，在SERPINA1中有四个），与预期相比，P/LP变体的富集超过三倍。本文最近发表在医学遗传学上。