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

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 这是一个修改后的提交K23奖博士Girish Nadkarni在伊坎医学院在山 西奈Nadkarni博士正在建立自己作为一个年轻的研究者在病人为导向的临床研究， 慢性肾脏疾病。该项目将试图改善肾脏疾病的风险预测和分层 在基线高遗传风险的少数人群中，由于载脂蛋白1（APOL 1）变异体而导致疾病进展。 候选人：本申请的主要目的是支持Girish Nadkarni博士的职业发展 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， 肾脏研究Nadkarni博士的职业目标是准确地对肾功能下降的患者进行风险分层， 未来有针对性地纳入评估新干预措施的临床试验。为了实现这些目标，博士。 Nadkarni组建了一个由主要导师Steven Coca博士领导的指导和咨询团队， 西奈山伊坎医学院教授兼临床研究主任， 博士Erwin Bottinger，医学教授，Charles Bronfman研究所前所长 个性化医疗。他的顾问团队包括Emilia Bagiella博士， 西奈山的生物统计学和纵向分析专家;博士Eiglion Kenny，助理教授， 遗传学和基因组学系，统计和人口遗传学专家; Avi Ma'ayan博士， 药理学和系统治疗学系副教授， 生物信息学和朱迪·曹博士，查尔斯·布朗夫曼个性化研究所的新任主任， 医学和转化遗传学的专家。他提出的培训计划主要集中在四个方面（1） 高级统计学和流行病学方法学;（2）生物标志物方法学;（3）计算 生物信息学和编程和（4）重点指导和职业发展。 环境：西奈山伊坎医学院是全国领先的研究，是最好的之一。 20所医学院获得NIH资助。ISMMS也被评为“世界十大最 大数据领域的创新公司”，因为它的计算资源和BioMe生物银行，其主要 建筑师是博廷格博士，目前由赵博士领导。 研究：少数民族患慢性肾脏疾病的风险更高。 这部分与APOL 1基因的风险变异有关，APOL 1基因存在于14%的人中， 非洲裔（包括非洲裔美国人[AAs]和西班牙裔拉丁美洲人[HLas]），但在非 西班牙白人尽管APOL 1高风险基因型通常与eGFR下降更快相关，但仅 约50%进展为ESRD，并且该组中的患者具有不同的肾功能下降率。 因此，这一组的危险分层较差，限制了早期干预。很大一部分弱势群体 风险增加的少数民族，预测肾功能下降的创新方法， 迫切需要遗传高危人群。因此，我们的具体目标是：（1）建立协会 的临床预测因子、生活方式因素和实验室参数， （2）建立一种新的血浆生物标志物， 炎症、损伤、血管损伤和纤维化，用于纵向eGFR下降的风险评估 在自我报告的AA/HLas与APOL 1高风险基因型;和（3）进行全面的，外部 验证性能最高的血浆生物标志物和传统预测因子，并推导风险 使用经验证的预测因子对自我报告的AA/HLa伴APOL 1患者的纵向eGFR下降进行聚类 高风险基因型目标1和2将使用最大的APOL 1风险受试者队列进行 已组装的变体（n=809）。目标3将使用四个外部队列进行，即范德比尔特BioVU 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研究（ARIC）和慢性肾功能不全队列研究（CRIC）。这些 整合遗传、生物标志物和电子病历临床信息的方法将成为基础， 为将来的工作调查有针对性的招募高风险患者在务实，随机对照试验 用于早期干预，将在K奖期结束前在R 01申请中提出。