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.

项目摘要/摘要此行政补充申请对PA-20-272的响应：“现有NIH的行政补充赠款和合作协议。”父母赠款是“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型目标和药物”（R01 AA030041-01）。父母赠款的目标利用基因组学和电子健康记录访问（EHR）数据的进展：1）阐明生物学与饮酒和饮酒有问题有关的网络（目标1和3）； 2）确定诺言用于重新利用酒精使用障碍的药物（AUD）（AIM 2）。在这里，我们建议对Kaiser Permanente Northern的完整EHR数据进行分析加利福尼亚州增加父母赠款的AIM 2C的严格性：估计AIM暴露药物的影响 2b使用退伍军人事务（VA）EHR的国家数据的饮酒变化。具体来说，我们正在评估脑穿透性L型钙通道阻滞剂，硝苯地平和felodipine的作用父r01中的VA数据，在这里我们提议还评估它们是否具有治疗效果在Kaiser EHR数据中作为补充中的验证。我们的目标1分析表明L型钙渠道是遗传支持的目标奥德来自Kaiser Permanente EHR的数据将大大增强父项目通过使我们能够评估R01调查结果的可复制性，即它们对外部人群的推广性 VA并检查了药物的性别特异性作用和剂量的特定作用。我们将采用一个活性启动器（非脑渗透剂L型钙通道阻滞剂），新用户设计，有前途得分匹配。我们将通过性别和剂量水平进行分层的后续分析。值得注意的是，关键 Kaiser Permanente人口的特征是，它在性别分布上比 VA人口约为10％的女性，对性别特异性药物的分析更为可行，并且因此克服了父母赠款的已知限制。该提案在原始父母赠款的目标范围内。我们相信这是一致的具有以下NIAAA行政补品标准：“增加患者，人口……应得的到……需要具有统计学意义的数据……”和“设备和相关服务的成本增加，例如，数据分析……”，凯撒永久团队包括Stacy Sterling博士（联合导演）和女士。首席统计分析师Vanessa Palzes来自成瘾和心理健康研究中心 Kaiser研究部。该团队与Lorenzo Leggio博士（R01合作者）紧密合作，最近在神经心理药理学上发表了螺内酯对螺旋酮影响的有前途得分分析饮酒。总而言之，提出的其他分析是高度可行的，将显着加强父母R01的发现。