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Presenter: Shari, Messinger, Miami, United States
Authors: Shari Messinger1,2, Franca Barton3
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Research design and statistical considerations in cell transplantation research-lessons from islet allograft transplantation
Shari Messinger1,2, Franca Barton3
1Division of Biostatistics, Department of Epidemiology and Public Health; 2Diabetes Research Institute, University of Miami, Miami, FL; 3Collaborative Islet Transplant Registry Coordinating Center, Emmes Corporation, Rockville, MD, United States
Objective: To characterize the statistical challenges specific to clinical islet cell transplantation research, and explore possible solutions.
Background: Clinical islet transplantation research, as with most areas of cell transplantation, can be broken down into two broadly defined areas. First is determining factors that associated with improved islet viability and yield, resulting in transplantable islet preparations. Impelling factors arise from donor characteristics, or relate to the procurement and isolation processes. These basic science investigations are then extended to investigations of factors that affect graft survival and function in vivo. This includes evaluation of factors specific to the transplant procedure, recipient characteristics and immunosuppressive strategies including patient-wise modifications mid-course.
Statistical Problems: Many experimental design and statistical problems present themselves in evaluating factors related to successful clinical islet transplantation, including: determining the experimental unit (recipient, donor, islet preparation), handling multiple infusions, choice of primary endpoint (insulin independence, glucose, C-peptide, HbA1c, metabolic function, quality of life, etc), and the low number of subjects relative to factors.
Investigations of islet processing as a basic science may not relate to outcomes of clinical transplantation. Standardization of outcome measures presents problems, ie. insulin requirement is actually a patient-doctor decision. Additionally, many of impelling factors specific to donor, procurement and processing, islet quality, recipient, and therapeutic regimen, which may be associated with clinical outcomes, may be mutually related, complicating sorting out their individual effects. Moreover, few of these factors are actually experimentally controllable, complicating hypothesis driven research.
Conclusions: Preliminary results of allogeneic human islet transplantation investigations should be used to guide rigorously controlled Phase II/III trials to definitively isolate the best islet processing procedures and patient management strategies. Investigations in to the basic science issues should be resolved before combining those results with clinical investigations. Whether each factor can be experimentally isolated remains a major practical obstacle.
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