The last decade witnessed dramatic growth in electronic health record (EHR) adoption, from less than 10% to nearly universal, in part due to more than $30 billion of federal government spending. Until recently, EHR implementation was limited to locally developed systems at large, academic healthcare organizations, which enabled extensive customization and novel research but had limited reproducibility and generalizability. Commercial EHRs, which now represent 95% of implemented EHRs, partially addressed problems related to system maintenance, long-term reliability, and variable annual costs. However, commercial systems significantly curtail the ability of informatics researchers at a single organization to experiment with different designs, configurations, and implementation strategies. Organizations adopting various commercial EHRs choose different configurations; use systems in distinct ways; and learn valuable, often costly lessons based on mistakes during such processes. These insights are rarely captured formally or disseminated widely, and most studies that do get published lack detailed implementation context. Combined, these limitations prevent healthcare organizations and EHR vendors from more rapidly and effectively adopting best practices and realizing the substantial patient safety improvement and cost savings that EHRs can provide. There is a critical need to conduct and report multi-institutional, large-scale applied clinical informatics research that is generalizable and can lead to knowledge that will improve EHR usage, provider satisfaction, and patient outcomes. This need requires standardized procedures that facilitate high quality research across EHR environments. The mission of the Clinical Informatics Research Collaborative (CIRCLE), and our long-term goal, is to identify and develop best practices for safe and effective health information technology (HIT) design, development, implementation, use, and evaluation. Based on needs identified through our previous work, our overall objective in this proposal is to develop standard procedures for carrying out multi-institutional applied clinical informatics research that will allow us to implement a series of new projects through a formal network of collaborators. Drawing from our prior experiences, we plan to achieve our overall objective by pursuing the following three specific aims: 1) Operationalize a network of applied clinical informatics collaborators, 2) Evaluate previously conducted collaborative applied clinical informatics research, and 3) Create Guidelines for Large-scale Applied Clinical Informatics Research (GLACIeR), a research statement to guide the conduct and reporting of collaborative applied clinical informatics research. This work has significant implications, given widespread current use of various commercially-developed EHRs. The ability to conduct multi-institutional research that improves informatics practices on a large scale can improve EHR implementations and enable the delivery of higher quality, safer, and more affordable healthcare overall.