Risk Clustering and Stratification in Genetically High-Risk Individuals Using Electronic Medical Records and Biomarkers

使用电子病历和生物标记对遗传高危个体进行风险聚类和分层

基本信息

批准号：
9180312
负责人：
Girish Nitin Nadkarni
金额：
$ 17.79万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9180312
关键词：
Address Admixture Advisory Committees Affect African African American Apolipoproteins Area Atherosclerosis Big Data Biochemical Markers Bioinformatics Biological Assay Biological Markers Biometry Blood Vessels Chronic Kidney Failure Chronic Kidney Insufficiency Clinical Clinical Research Clinical Trials Coca Communities Computerized Medical Record Data Development Discrimination Disease Disease Progression Early Diagnosis Early Intervention Early identification End stage renal failure Endostatins Endothelin-1 Enrollment Environment Epidemiology Fibrosis Frequencies Funding Future Genes Genetic Genetic Markers Genetic Risk Genetic screening method Genomics Glomerular Filtration Rate Goals Hispanics Individual Inflammation Injury Institutes Interleukin-18 Intervention K-Series Research Career Programs Kidney Kidney Diseases Kidney Failure Laboratories Latino Life Style Link Literature Measurement Medicine Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Methodology Methods Minority Monocyte Chemoattractant Protein-1 Names Nephrology Not Hispanic or Latino Participant Pathway interactions Patient Self-Report Patients Pharmacology Plasma Plasma Proteins Population Population Genetics Prevalence Process Protocols documentation Publishing Randomized Controlled Trials Renal function Research Research Infrastructure Research Personnel Risk Risk Estimate Risk Factors Sampling Specimen Stratification System TNF gene TNFR-Fc fusion protein TNFRSF1A gene Testing Therapeutic Training Tubular formation United States United States National Institutes of Health Validation Variant Work base biobank biomarker panel career career development clinical predictors cohort computing resources disorder risk ethnic minority population follow-up functional decline genetic variant genomic biomarker high risk improved innovation lifestyle factors longitudinal analysis medical schools mid-career faculty novel novel therapeutic intervention patient oriented patient stratification patient subsets personalized medicine professor programs rat KIM-1 protein risk variant translational genetics

项目摘要

PROJECT SUMMARY/ABSTRACT This is a revised submission for a K23 award by Dr. Girish Nadkarni at the Icahn School of Medicine at Mount Sinai. Dr. Nadkarni is establishing himself as a young investigator in patient oriented clinical research of chronic kidney disease. This project will try to improve risk prediction and stratification for kidney disease progression in minority populations at baseline high genetic risk due to Apolipoprotein1 (APOL1) variants. Candidate: The primary objective of this application is to support Dr. Girish Nadkarni's career development into an independent investigator in the field of leveraging biomarkers, genomics and “big data” approaches for renal research. Dr. Nadkarni's career goal is to accurately risk stratify patients for renal functional decline for future targeted enrolment into clinical trials evaluating novel interventions. To achieve these goals, Dr. Nadkarni has assembled a mentoring and advisory team led by a primary mentor, Dr. Steven Coca, Associate Professor and Director of Clinical Research at the Icahn School of Medicine at Mount Sinai, and a co-mentor Dr. Erwin Bottinger, Professor of Medicine and former Director of The Charles Bronfman Institute of Personalized Medicine. His advisory team consists of Dr. Emilia Bagiella, Professor in the Division of Biostatistics at Mount Sinai and an expert in longitudinal analysis; Dr. Eimear Kenny, Assistant Professor in the Department of Genetics and Genomics and an expert in statistical and population genetics; Dr. Avi Ma'ayan, an Associate Professor in the Department of Pharmacology and Systems Therapeutics and an expert in bioinformatics and Dr. Judy Cho, the incoming director of the Charles Bronfman Institute of Personalized Medicine and an expert in translational genetics. His proposed training plan focuses on four areas (1) Advanced Statistical and Epidemiological Methodology; (2) Biomarker Methodology; (3) Computational Bioinformatics and Programming and (4) Focused mentorship and career development. Environment: Icahn School of Medicine at Mount Sinai is a national leader in research and is one of the top 20 medical schools in NIH funding. ISMMS was also named as one of the "The World's Top 10 Most Innovative Companies In Big Data" due to its computing resources and the BioMe Biobank, whose primary architect is Dr.Bottinger and is currently led by Dr. Cho. Research: Ethnic minorities are at higher risk of both development and progression of chronic kidney disease. This has been linked in part to risk variants in the APOL1 gene that are present in up to 14% in populations of African descent (including African Americans [AAs] and Hispanic Latinos [HLas]) but are absent in non- Hispanic Whites. Although APOL1 high-risk genotype is, in general, associated with faster eGFR decline, only about 50% progress to ESRD and patients within this group have differing rates of renal functional decline. Thus, risk stratification within this group is poor, limiting early intervention. With a large proportion of vulnerable ethnic minorities at increased risk, innovative methods for predicting renal function decline within this genetically high-risk group are urgently needed. Therefore, our specific aims are: (1) Establish associations of clinical predictors, lifestyle factors and laboratory parameters with longitudinal eGFR decline in AA/HLas with APOL1 high-risk genotype; (2) To develop a novel plasma biomarker panel assessing inflammation, injury, vascular insult and fibrosis, for risk prognostication of longitudinal eGFR decline in self-reported AA/HLas with APOL1 high-risk genotype; and (3) To conduct comprehensive, external validation of the highest performing plasma biomarkers and traditional predictors and derive risk clusters using validated predictors for longitudinal eGFR decline in self-reported AA/HLa's with APOL1 high-risk genotype. Aims 1 and 2 will be conducted using the largest cohort of participants with APOL1 risk variants ever assembled (n=809). Aim 3 will be conducted using four external cohorts, the Vanderbilt BioVU cohort, the Genetic testing to Understand and Address Renal Disease Disparities (GUARDD) study, the Atherosclerosis Risk in Communities (ARIC) study and the Chronic Renal Insufficiency Cohort (CRIC). These approaches integrating genetic, biomarker and electronic medical record clinical information, will form the basis for future work investigating targeted enrolment of high-risk patients in pragmatic, randomized controlled trials for early interventions, which will be proposed in an R01 application before the end of the K award period.

项目概要/摘要这是芒特伊坎医学院的 Girish Nadkarni 博士提交的 K23 奖项的修订提交西奈 (Nadkarni) 博士正在将自己定位为以患者为导向的临床研究领域的年轻研究者。该项目将尝试改进肾脏疾病的风险预测和分层。由于载脂蛋白 1 (APOL1) 变异，少数群体处于基线高遗传进展风险。候选人：此申请的主要目的是支持 Girish Nadkarni 博士的职业发展成为利用生物标志物、基因组学和“大数据”方法领域的独立研究者 Nadkarni 博士的职业目标是准确对患者肾功能下降的风险进行分层。未来有针对性地参加评估新干预措施的临床试验。 Nadkarni 组建了一个指导和咨询团队，由主要导师 Steven Coca 博士（副教授）领导西奈山伊坎医学院教授兼临床研究主任，联合导师 Erwin Bottinger 博士，医学教授、查尔斯·布朗夫曼研究所前所长他的顾问团队由医学部教授 Emilia Bagiella 博士组成。西奈山生物统计学家、纵向分析专家 Eimear Kenny 博士，助理教授遗传学和基因组学系、统计和群体遗传学专家 Avi Ma'ayan 博士；药理学和系统治疗学系副教授，专家生物信息学和查尔斯·布朗夫曼个性化研究所即将上任所长 Judy Cho 博士医学和转化遗传学专家。他提出的培训计划侧重于四个领域 (1)。高级统计和流行病学方法；（2）生物标志物方法；（3）计算生物信息学和编程以及 (4) 重点指导和职业发展。环境：西奈山伊坎医学院在研究方面处于全国领先地位，是顶尖的医学院之一 20所医学院还被NIH评为“世界十大最受资助的医学院”之一。大数据领域的创新型公司”得益于其计算资源和 BioMe 生物银行，其主要建筑师是 Bottinger 博士，目前由 Cho 博士领导。研究：少数族裔患慢性肾病的风险较高。这在一定程度上与 APOL1 基因的风险变异有关，该基因在 14% 的人群中存在。非洲裔（包括非裔美国人 [AAs] 和西班牙裔拉丁裔 [HLas]），但在非非裔美国人中不存在尽管 APOL1 高风险基因型一般与 eGFR 下降更快有关，但仅是西班牙裔白人。大约 50% 的患者进展为 ESRD，并且该组患者的肾功能下降率不同。因此，该群体内的风险分层较差，限制了大部分弱势群体的早期干预。少数民族风险增加，预测肾功能衰退的创新方法因此，我们的具体目标是：（1）建立协会。临床预测因素、生活方式因素和实验室参数与纵向 eGFR 下降的关系具有APOL1高危基因型的AA/HLas；（2）开发一种新型血浆生物标志物组评估；炎症、损伤、血管损伤和纤维化，用于纵向 eGFR 下降的风险预后在自我报告的具有 APOL1 高风险基因型的 AA/HLas 中；以及 (3) 进行全面的外部评估；验证最高性能的血浆生物标志物和传统预测因子并得出风险使用经验证的预测因子对自我报告的 AA/HLa 中的纵向 eGFR 下降与 APOL1 进行聚类高风险基因型的目标 1 和 2 将使用最大的 APOL1 风险参与者群体进行。已组装的变体（n=809）将使用四个外部队列（Vanderbilt BioVU）进行。队列，了解和解决肾脏疾病差异的基因检测（GUARDD）研究，社区动脉粥样硬化风险 (ARIC) 研究和慢性肾功能不全队列 (CRIC)。整合遗传、生物标志物和电子病历临床信息的方法将构成基础对于未来的工作，调查在务实的随机对照试验中有针对性地招募高风险患者早期干预，将在 K 奖励期结束前在 R01 申请中提出。