title: Mechanistic modeling of hemoglobin glycation and red blood cell kinetics enables personalized diabetes monitoring.
abstract: The amount of glycated hemoglobin (HbA1c) in diabetic patients' blood provides the best estimate of the average blood glucose concentration over the preceding 2 to 3 months. It is therefore essential for disease management and is the best predictor of disease complications. Nevertheless, substantial unexplained glucose-independent variation in HbA1c makes its reflection of average glucose inaccurate and limits the precision of medical care for diabetics. The true average glucose concentration of a nondiabetic and a poorly controlled diabetic may differ by less than 15 mg/dl, but patients with identical HbA1c values may have true average glucose concentrations that differ by more than 60 mg/dl. We combined a mechanistic mathematical model of hemoglobin glycation and red blood cell kinetics with large sets of within-patient glucose measurements to derive patient-specific estimates of nonglycemic determinants of HbA1c, including mean red blood cell age. We found that between-patient variation in derived mean red blood cell age explains all glucose-independent variation in HbA1c. We then used our model to personalize prospective estimates of average glucose and reduced errors by more than 50% in four independent groups of greater than 200 patients. The current standard of care provided average glucose estimates with errors >15 mg/dl for one in three patients. Our patient-specific method reduced this error rate to 1 in 10. Our personalized approach should improve medical care for diabetes using existing clinical measurements.
authors.affiliation: Center for Systems Biology and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Malka
authors.affiliation: Diabetes Center, Massachusetts General Hospital, Boston, MA 02114, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Nathan
authors.affiliation: Center for Systems Biology and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. john_higgins@hms.harvard.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Higgins
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D015190:Blood Glucose Self-Monitoring; D003920:Diabetes Mellitus / Q000097:blood* / Q000175:diagnosis*; D004912:Erythrocytes / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D057285:Precision Medicine
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin