The study was conducted by the Diabetes Research in Children Network (DirecNet) at five clinical centers. Subjects were participating in another study, conducted in Clinical Research Centers (CRCs), that was evaluating the counter-regulatory response to hypoglycemia in younger (3 to <8 years old) and older (12 to <18 years old) children. Eligibility criteria included a clinical diagnosis of type 1 diabetes (T1D) of ≤1 year in duration, glycosylated hemoglobin level of ≤10.0%, and use of an insulin pump. The Institutional Review Boards at each center and a Data and Safety Monitoring Board approved the study protocol, consent form, and assent form. A parent or guardian and each subject 7 years and older gave written consent and assent, respectively.
Subjects initially used a Guardian RT for approximately 1 week at home. Approximately half of the subjects were asked to insert a new sensor 4 days before the CRC admission, and the other half 2 days before the admission. Glucose levels were checked at least four times per day with a new One Touch® Ultra® meter (LifeScan, Milpitas, CA) that was provided by the study.
Each subject was then hospitalized overnight for about 18
h in a CRC. For subjects of sufficient size to accommodate another device, a second Guardian RT sensor was inserted. During insulin-induced hypoglycemia in which insulin was infused subcutaneously from the subject's insulin pump, the glucose level was checked with the Ultra meter using venous blood every 15
min until the glucose level reached 100
mg/dL and then every 5–10
min. The test ended when the glucose level was <60
mg/dL, and then the subject was treated with intravenous glucose. Blood samples were collected at the beginning of the test, when the meter glucose level was <90, <80, < 70, and <60
mg/dL, and 15
min following treatment. For subjects of sufficient weight to accommodate the volume of blood required, venous blood samples for laboratory serum glucose concentration determinations were taken every 30
min during the hospitalization and every 15
min for 2
h after dinner. Serum glucose concentrations from these samples were measured at the DirecNet Central Biochemistry Laboratory at the University of Minnesota using a hexokinase enzymatic method.1,2
Accuracy analyses were performed separately for inpatient and outpatient Guardian RT use. Laboratory serum glucose values were used as the reference during the inpatient CRC visit, and Ultra meter glucose measurements were used as the reference during home use. Suspected outliers in the meter values where the rate of change was >5
mg/dL/min or where a repeat test was done within 10
min were excluded from analysis. In a prior study, we found that the Ultra meter had a high degree of accuracy.3
Each reference glucose value was paired to the closest Guardian RT reading within 2.5
min. The following were computed for each Guardian–reference pair: difference (Guardian RT value minus reference value), absolute difference (absolute value of difference; AD), and relative AD (AD divided by reference value, expressed as a percentage; RAD). The difference measure incorporates the direction of the error so that pairs with the sensor reading high cancel out pairs with the sensor reading low. The median difference therefore evaluates whether there is any bias for the sensor to read systematically high or low. The AD and RAD values use the absolute value of the difference between the sensor value and the reference value, ignoring the direction of the error. These measures reflect the magnitude of the error without regard to whether the sensor value was higher or lower than the reference value. Each pair was also evaluated to determine whether the sensor value met the International Organization for Standardization (ISO) criteria for home glucose meters (for reference glucose value ≤75
mg/dL, meter value within 15
mg/dL; for reference glucose value >75
mg/dL, meter value within 20%; hereafter referred to as the “ISO criteria”).4
Summary statistics (e.g., median and percentages) were calculated by pooling all paired values. Median values were reported instead of means because of the skewed distribution. The bootstrap technique (resampling subjects with replacement)5
was used to account for the within-subject correlation in the statistical comparisons and calculation of confidence intervals.
The glucose excursions during the insulin-induced hypoglycemia test (drop from baseline to nadir) for the laboratory reference values and the Guardian RT were compared. The Guardian RT nadir glucose was the extrapolated nadir in 20
min following treatment and was calculated using 15-min rate of change of the Guardian RT values. The rate of change for laboratory reference values was defined from the blood sample at the meter glucose level <90
mg/dL to the first time the laboratory glucose value dropped below 70
mg/dL (approximately 90
mg/dL to <70
mg/dL) and was compared with the rate of change of Guardian RT values in the same period.
In the post-dinner glucose excursion (rise from baseline to peak), the Guardian RT peak glucose was defined as the maximum glucose value from baseline until 30
min following the laboratory peak (to allow for a possible lag). The rate of change was defined from baseline until the peak.
For subjects using two Guardian RT sensors simultaneously in the CRC, precision was evaluated by pairing each Guardian RT sensor value with the closest value that was within
min and computing the RAD.