Precision Pharmacogenomic Perioperative Prediction

背景：VA手术质量改进计划（VASQIP）预测了重要的 术后结局和共享来自高性能部位的过程改善， 性能网站，以不断提高手术效果。VASQIP非常成功， 在私营部门实施，并一直持续到今天。拟议的研究将增加药物基因组学 从百万退伍军人计划（MVP）到VASQIP。此外，VASQIP还与 VA国家人工智能研究所（NAII）从其他VA数据库中添加更多表型数据 包括VASQIP、集中式交互表型组学资源（CIPHER）、VA信息学和计算 基础设施（芬奇）和企业数据仓库。此表型数据也将添加到 VASQIP和机器学习/人工智能将用于在单独的项目中更新VASQIP 将同时进行。 意义：药物基因组学检查个体的基因，影响药物代谢，药物 靶点、药物转运或药物免疫应答以及对药物不良事件和治疗的影响 有效性药物基因组学可以解释治疗反应的变化，这是常见的， 临床实践药物基因组学与更差和更好的结果和成本有关 在许多临床环境中有效。药物基因组学数据包含在499个FDA药物标签中。 尽管药物基因组学检测的益处得到了承认，但这种检测并不常规。 一般在VA内完成，而不是专门用于手术。 创新与影响：拟议的研究有几种创新方法。应用 药物基因组学数据到手术结果，使用机器学习和人工智能来添加 表型数据的VASQIP计划，目标是迅速实施的结果到病人护理， 优化以患者为中心的决策和结果都是创新的。 具体目的：1）确定药物基因组学风险与接受 血管外科和心脏外科在过去10年中已建立的（1级和2级）药物/基因集。（二） 确定接受血管手术的个体中药物基因组学风险与结局的相关性， 过去10年中，心脏手术用于非确定（3级）药物/基因集。3)评估研究频率 药物使用和药物基因组学基因的存在，为未来的研究建立动力模型。4)识别高风险 可能受益于药物基因组学检测的亚组。 方法：这是一项回顾性队列研究，将使用标准VASQIP变量和结局。 基线分析将使用线性回归或考克斯比例风险模型，并将控制患者 基线特征和手术因素，使用匹配或反向加权的倾向评分。 机器学习方法，如人工神经网络，分类和回归树，或集成 学习将用于改进预测，并解释非线性关系和相互作用， 潜在的大量药物基因组学特征。 后续步骤/实施：拟议研究的结果将用于更新所有VASQIP 手术，然后现场实施可以发生用于真实的时间临床决策支持。高风险患者 将确定将受益于术前药物基因组学检测的亚组， 干预研究。

Background: The VA Surgical Quality Improvement Program (VASQIP) predicts risk for important postoperative outcomes and shares process improvements from high performance sites with lower performance sites to continuously improve surgical outcomes. The VASQIP was so successful it was implemented in the private sector and continues today. The proposed research will add pharmacogenomic data from the Million Veterans Program (MVP) to the VASQIP. In addition, the VASQIP is collaborating with the VA National Artificial Intelligence Institute (NAII) to add more phenotype data from other VA databases including VASQIP, Centralized Interactive Phenomics Resource (CIPHER), VA Informatics and Computing Infrastructure (VINCI), and the Corporate Data Warehouse. This phenotype data will also be added to the VASQIP and machine learning/ artificial intelligence will be used to update the VASQIP in a separate project that will be done in parallel. Significance: Pharmacogenomics examines an individual person’s genes that affect drug metabolism, drug target, drug transport, or drug immune response and the impact on adverse drug events and treatment effectiveness. Pharmacogenomics can explain the variation in treatment response that is commonly seen in clinical practice. Pharmacogenomics has been associated with both worse and improved outcomes and cost effectiveness in a number of clinical settings. Pharmacogenomic data is included on 499 FDA drug labels. Despite this acknowledgement of the benefits of Pharmacogenomic testing, such testing is not routinely completed within the VA in general, and not for surgery specifically. Innovation & Impact: There are several innovative approaches to the proposed research. Applying pharmacogenomic data to surgical outcomes, using machine learning and artificial intelligence to add phenotypic data to the VASQIP program with the goal of rapidly implementing the results into patient care to optimize patient centered decision making and outcomes are all innovative. Specific Aims: 1) Identify pharmacogenomic risk associations with outcomes among individuals receiving vascular surgery and cardiac surgery the past 10 years for established (tier 1 and 2) drug/ gene sets. 2) Identify pharmacogenomic risk associations with outcomes among individuals receiving vascular surgery and cardiac surgery the past 10 years for non-established (tier 3) drug/ gene sets. 3) Assess frequency of study drug usage and presence of pharmacogenomic genes for power modeling future studies. 4) Identify high-risk subgroups that may benefit from pharmacogenomic testing. Methodology: This is a retrospective cohort study that will use the standard VASQIP variables and outcomes. Baseline analysis will use linear regression or Cox’s proportional hazards model and will control for patient baseline characteristics and surgical factors using propensity scores with matching or inverse weighting. Machine learning methods such as artificial neural networks, classification and regression trees, or ensemble learning will be used to improve predictions and account for nonlinear relationships and interactions among the potentially large set of pharmacogenomic features. Next Steps/Implementation: The results of the proposed research will be used to update all VASQIP surgeries, then field implementation can occur for real time clinical decision support. High risk patient subgroups will be identified that would benefit from preoperative pharmacogenomic testing and further intervention studies.