Leveraging genetic and electronic health records data to identify novel targets and drugs for treating alcohol

利用遗传和电子健康记录数据来确定治疗酒精的新靶点和药物

基本信息

批准号：
10888495
负责人：
Joshua Charles Gray
金额：
$ 10.06万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10888495
关键词：
Administrative Supplement Adult Affect Alcohol abuse Alcohol consumption Alcohols Algorithms Biological Brain Calcium Channel Blockers California Caring Catalogs Characteristics Chromatin Chronic Disease Clinical Trials Data Data Analyses Data Set Development Diagnosis Disease Drug Exposure Drug Interactions Drug Targeting Electronic Health Record Equipment Evaluation Exposure to FDA approved Felodipine Female Future Gene Structure Genes Genetic Genome Genomics Goals Grant Health Impairment Integrated Health Care Systems L-Type Calcium Channels Lead Link Measures Medical Mental Health Methods Molecular Conformation National Institute on Alcohol Abuse and Alcoholism Nifedipine Occupational Occupations Ontology Parents Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacoepidemiology Phenotype Population Proteins Psychiatry Publishing Quantitative Trait Loci Reporting Research Review Literature Risk Scoring Method Services Sex Distribution Single Nucleotide Polymorphism Spironolactone Testing Therapeutic U-Series Cooperative Agreements United States Department of Veterans Affairs United States Food and Drug Administration United States National Institutes of Health Untranslated RNA Validation Work active comparator addiction alcohol risk alcohol use disorder causal variant cohort cost design dosage drinking drug candidate drug development drug repurposing follow-up genetic analysis genome wide association study genome-wide improved innovation multiple omics neuropsychopharmacology novel parent grant parent project pre-clinical preclinical study psychogenetics sex social success treatment effect work-study

项目摘要

PROJECT SUMMARY/ABSTRACT This administrative supplement application responds to PA-20-272: “Administrative Supplements to Existing NIH Grants and Cooperative Agreements.” The parent grant is “Leveraging genetic and electronic health record data to identify novel targets and drugs for treating alcohol use disorder” (R01 AA030041-01). The parent grant aims to leverage advances in genomics and access to electronic health record (EHR) data to: 1) elucidate biological networks linked to alcohol consumption and problematic alcohol use (Aims 1 and 3); and 2) identify promising drugs for repurposing to treat alcohol use disorder (AUD) (Aim 2). Here, we propose to conduct analyses of complementary EHR data from Kaiser Permanente Northern California to increase the rigor of Aim 2c of the parent grant: Estimate the effect of exposure to drugs from Aim 2b on changes in alcohol consumption using national data from the Veterans Affairs (VA) EHR. Specifically, we are evaluating the effect of the brain penetrant L-type calcium channel blockers, nifedipine and felodipine, in the VA data in the parent R01 and here we are proposing to also evaluate whether they have treatment effects in the Kaiser EHR data as a validation in the supplement. Our Aim 1 analyses have shown that L-type calcium channels are genetically supported targets with theoretical and preclinical support for repurposing for treating AUD. The inclusion of data from Kaiser Permanente EHR will substantially enhance the parent project by enabling us to evaluate the replicability of R01 findings, their generalizability to a population outside the VA and examine sex-specific effects and dosage specific effects of the medication. We will employ an active-comparator (non-brain-penetrant L-type calcium channel blockers), new-user design, with propensity score matching. We will conduct follow-up analyses stratified by sex and by dosage level. Of note, a critical characteristic of the Kaiser Permanente population is that it is much more balanced on sex distribution than the VA population, which is ~10% female, making analyses of sex-specific medication effects more feasible and therefore overcoming a known limitation of the parent grant. This proposal is within the scope of the aims from the original parent grant. We believe it is consistent with the following NIAAA criteria for administrative supplements: “Addition of patients, populations… due to… a need for statistically significant data…” and “Increased cost of equipment and related services, e.g., data analysis…” Of note, the Kaiser Permanente team includes Dr. Stacy Sterling (Co-Director) and Ms. Vanessa Palzes, lead Statistical Analyst, from the Center for Addiction and Mental Health Research within the Kaiser Division of Research. This team has worked closely with Dr. Lorenzo Leggio (Collaborator on the R01), recently publishing in Neuropsychopharmacology a propensity-score analysis of the effect of spironolactone on alcohol consumption. In summary, the proposed additional analyses are highly feasible and will significantly strengthen findings from the parent R01.

项目概要/摘要该行政补充申请响应 PA-20-272：“现有 NIH 的行政补充赠款和合作协议。母赠款是“利用遗传和电子健康记录数据” 确定治疗酒精使用障碍的新靶点和药物”（R01 AA030041-01）。利用基因组学的进步和电子健康记录 (EHR) 数据的获取来：1) 阐明生物学与饮酒和有问题的饮酒有关的网络（目标 1 和 3）和 2）确定了有前景的网络；重新利用药物治疗酒精使用障碍 (AUD)（目标 2）。在这里，我们建议对 Kaiser Permanente Northern 的补充 EHR 数据进行分析加州将提高家长补助金 Aim 2c 的严格性：估计接触 Aim 药物的影响 2b 使用退伍军人事务部 (VA) EHR 的国家数据了解酒精消费的变化。正在评估脑渗透性 L 型钙通道阻滞剂硝苯地平和非洛地平在母体R01中的VA数据，这里我们建议也评估它们是否有治疗效果 Kaiser EHR 数据作为补充剂中的验证，我们的目标 1 分析表明 L 型钙。通道是遗传支持的靶点，具有重新利用治疗的理论和临床前支持 AUD。纳入 Kaiser Permanente EHR 的数据将大大增强母项目的质量。通过使我们能够评估 R01 研究结果的可重复性及其对外部人群的普遍适用性 VA 并检查药物的性别特异性效应和剂量特异性效应。主动比较器（非脑渗透性L型钙通道阻滞剂），新用户设计，有倾向值得注意的是，我们将按性别和剂量水平进行后续分析。凯撒永久人口的特点是性别分布比普通人口要均衡得多 VA 人群中约 10% 为女性，这使得对特定性别药物效果的分析更加可行和因此克服了母基金的已知限制。该提案在原始母基金的目标范围内，我们认为它是一致的。遵循以下 NIAAA 行政补充标准：“患者、人群的增加……由于 ……需要统计上重要的数据……”和“设备和相关服务的成本增加，例如，数据分析……”值得注意的是，Kaiser Permanente 团队包括 Stacy Sterling 博士（联合主任）和 Ms. Vanessa Palzes，首席统计分析师，来自成瘾和心理健康研究中心凯撒研究部该团队与 Lorenzo Leggio 博士（R01 的合作者）密切合作，最近在 Neuropsychopharmacology 上发表了螺内酯影响的倾向评分分析总之，拟议的额外分析是高度可行的，并且将显着。强化母体 R01 的发现。