PROJECT SUMMARY / ABSTRACT Donated human red blood cells (RBC) are processed and stored in blood banks for up to 42 days. During storage, RBC undergo biochemical and biophysical changes: bioreactive substances from RBC breakdown and from the storage system itself accumulate over time. There continues to be concern that transfusion of this heterogeneous product produces adverse clinical effects. Four recently completed large randomized controlled trials (RCT) addressed clinical impacts of RBC storage age. These RCT found no significant deleterious effects of longer-stored RBC transfusion in contrast to earlier observational literature often associating longer-stored RBC with increased morbidity/mortality. In addition, there was a non-significant trend toward worse outcomes with shorter-stored RBC. However, these RCT did not individually address safety of RBC >35 days or include sufficient numbers of subjects receiving RBC at either storage age extreme (<7 days or >35 days) to identify effects of RBC transfusion at these limits. Finally, recent biomarker studies defining the evolving metabolomics age of RBC during storage suggest RBC transfused in the mid-storage window may be preferable to either shorter or longer storage age extreme. Conventional meta-analysis methodology combines multiple trials' data to reveal new information. However, meta-analyses of RBC storage age trials have been hampered by study variability and thus unable to analyze the impact of storage age extremes. The most powerful technique to explore the full implications of trial results is Individual Patient Data Meta-Analysis (IPDMA), which allows direct comparison of each subject's data and outcomes across trials. We propose performing IPDMA across the four RCTs of RBC storage age in a unique international collaboration to explore the relationship between age of transfused RBC and mortality/morbidity. We will identify and refine common data elements to extract comparable Individual Patient Data (IPD) from the 4 largest RCT: ABLE, RECESS, INFORM and TRANSFUSE. We will merge IPD from nearly 33,000 subjects, the largest number transfused with RBC at storage age extremes to date, to optimize comparison of outcomes, such as mortality. The primary analysis will use IPDMA to assess the effect of longer vs. shorter stored RBC on time to death through 28 days from the first RBC transfusion, preserving the benefits of randomization while increasing statistical power. We will also use IPDMA to explore the hypothesis that RBC transfusion at either storage extreme is associated with other adverse outcomes. We will additionally investigate whether mid-range storage duration RBC could be associated with better outcomes as suggested from metabolomics studies. If exploration of the combined datasets suggests either extreme of storage age is associated with worse clinical outcomes, then global blood bank RBC practice, storage methods and/or transfusion practice might be dramatically impacted. S...