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

项目摘要/摘要 此行政补充申请响应PA-20-272：“对现有NIH的行政补充 赠款和合作协议“。父母的资助是“利用遗传和电子健康记录数据 寻找治疗酒精使用障碍的新靶点和药物“(R01 AA030041-01)。家长助学金的目的是 利用基因组学的进步和电子健康记录(EHR)数据的访问来：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)确定有希望的 用于改变用途治疗酒精使用障碍的药物(目标2)。 在这里，我们建议对来自Kaiser Permanente Northern的补充EHR数据进行分析 加州将提高父母拨款的AIM 2c的严格性：评估接触AIM药物的影响 2B使用退伍军人事务部(退伍军人事务部)EHR的国家数据说明酒精消费的变化。具体来说，我们 正在评估脑穿透性L类钙通道阻滞剂硝苯地平和非洛地平在高血压患者中的作用 在亲本R01中的VA数据，在这里我们建议也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 经络是基因支持的靶点，具有理论和临床前支持，用于治疗 澳元。纳入Kaiser Permanente EHR的数据将大大增强父项目 通过使我们能够评估R01研究结果的可复制性，它们对外部人群的普适性 并检查药物的性别特异性效应和剂量特异性效应。我们将聘请一名 主动比较器(非脑穿透型L钙通道阻滞剂)，新用户设计，有倾向性 分数匹配。我们将按性别和剂量水平进行后续分析。值得注意的是，一个关键的 Kaiser Permanente种群的特点是在性别分布上比 退伍军人中约10%为女性，这使得对特定性别的药物效果的分析更加可行和 因此克服了父母拨款的已知限制。 这项建议在原家长拨款的目标范围内。我们相信这是一致的 NIAAA的行政补充标准如下：“增加患者，人口…到期 到…对统计意义重大的数据…的需求“以及“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(联席主任)和M女士。 Vanessa Palze，来自成瘾和心理健康研究中心的首席统计分析师 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《神经精神药理学》上发表了一篇关于螺内酯影响的倾向-分数分析。 饮酒。总而言之，拟议的额外分析是高度可行的，并将显著 加强来自父R01的调查结果。

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.