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

• 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
• 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; 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

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.

项目摘要/摘要 这是Mount的伊坎医学院的Girish Nadkarni博士颁发的K23奖项的修订。 西奈。 Nadkarni博士正在建立自己是年轻的研究者 慢性肾脏疾病。该项目将尝试改善肾脏疾病的风险预测和分层 载脂蛋白1（APOL1）变体引起的基线高遗传风险的少数族裔人群的进展。 候选人：本申请的主要目的是支持Girish Nadkarni博士的职业发展 进入利用生物标志物，基因组学和“大数据”方法领域的独立研究者 肾脏研究。 Nadkarni博士的职业目标是准确冒险将患者分层以肾功能下降的措施 未来的目标是评估新干预措施的临床试验。为了实现这些目标，博士 纳德卡尼（Nadkarni）召集了一个由主要心理的心理和咨询团队，助理史蒂文·可可（Steven Coca）博士 西奈山伊坎医学院的临床研究教授兼临床研究主任和一个联合学者 医学教授兼前查尔斯·布朗夫曼学院的前主任Erwin Bottinger博士 个性化医学。他的顾问团队由艾米莉亚·巴吉拉（Emilia Bagiella）博士组成 西奈山的生物统计学和纵向分析专家； Eimear Kenny博士，助理教授 遗传学和基因组学系以及统计和人口遗传学专家； Avi Ma'ayan博士， 药理学和系统治疗系的副教授，专家 生物信息学和查尔斯·布朗夫曼个性化研究所的即将上任的主任朱迪·乔（Judy Cho）博士 医学和翻译遗传学专家。他提出的培训计划着重于四个领域（1） 先进的统计和流行病学方法论； （2）生物标志物方法； （3）计算 生物信息学和编程以及（4）集中的心态和职业发展。 环境：西奈山的伊坎医学院是研究的国家领导者，是最重要的 NIH资助的20所医学院。 ISMM也被命名为“世界上最十大的十大之一 大数据中的创新公司“由于其计算资源和生物群落生物库，其主要 建筑师是Bottinger博士，目前由Cho博士领导。 研究：少数民族的发展和进展的慢性肾脏疾病风险更高。 这与APOL1基因中的风险变异的一部分相关 非洲血统（包括非裔美国人[AAS]和西班牙裔拉丁裔[HLAS]），但在非 - 西班牙裔白人。尽管APOL1高风险基因型通常与EGFR下降速度更快有关 ESRD的进展约为50％，该组中的患者的肾功能下降率不同。 这是该组内的风险分层很差，限制了早期干预。很大一部分脆弱 风险增加的少数民族，预测肾功能下降的创新方法 迫切需要基因高风险的群体。因此，我们的具体目的是：（1）建立关联 临床预测因素，生活方式因素和实验室参数的纵向EGFR下降 AA/HLA具有APOL1高风险基因型； （2）开发一种新型的等离子体生物标志物面板评估 发炎，损伤，血管损伤和纤维化，用于纵向EGFR下降的风险编程 在具有APOL1高风险基因型的自我报告的AA/HLA中； （3）进行全面的外部 验证性能最高的等离子体生物标志物和传统预测因子并获得风险 使用经过验证的预测因子的群集用于自我报告的AA/HLA的纵向EGFR使用Apol1 高风险基因型。 AIM 1和2将使用具有APOL1风险的最大参与者队列进行 变体曾经组装（n = 809）。 AIM 3将使用四个外部队列进行Vanderbilt Biovu进行 队列，了解和解决肾脏疾病差异和解决肾脏疾病差异的基因检测（Guardd）研究， 社区研究（ARIC）研究和慢性肾功能不全队列（CRIC）的动脉粥样硬化风险。这些 整合遗传，生物标志物和电子病历临床信息的方法将形成基础 对于未来的工作，调查了务实的随机对照试验中高危患者的有针对性入学 对于早期干预措施，该干预措施将在K颁奖期结束之前在R01申请中提出。