Annette Baumstark

System Accuracy Evaluation of 27 Blood Glucose Monitoring Systems According to DIN EN ISO 15197

BACKGROUND Blood glucose (BG) monitoring systems enable diabetes patients to effectively control and adjust their therapy. BG monitoring systems with a Conformité Européenne (CE) label should meet the standard DIN EN ISO 15197:2003: > or =95% of the BG results shall fall within +/-15 mg/dL of the reference method at BG concentrations <75 mg/dL and within +/-20% at BG concentrations > or =75 mg/dL. We intended to verify if BG monitoring systems with a CE label fulfill these minimum accuracy requirements. METHODS We evaluated 27 BG monitoring systems from 18 manufacturers for system accuracy according to DIN EN ISO 15197:2003. Twenty-four systems were compared with the glucose oxidase reaction (YSI 2300 glucose analyzer [YSI Life Sciences, Yellow Springs, OH]) and three systems with the hexokinase reaction (Hitachi 917 [Roche Diagnostics GmbH, Mannheim, Germany]). Duplicate measurements of 100 blood samples with a defined distribution of BG concentrations from 20 mg/dL to 600 mg/dL from > or =100 subjects were included in the evaluation. RESULTS Sixteen of the 27 BG monitoring systems fulfilled the minimum accuracy requirements of the standard, i.e., > or =95% of their results showed the minimum acceptable accuracy. Overall, the mean percentage of results showing the minimum acceptable accuracy was 95.2 +/- 5.2%, ranging from 80.0% to 100.0%. CONCLUSIONS More than 40% of the evaluated BG monitoring systems did not fulfill the minimum accuracy requirements of DIN EN ISO 15197:2003. As inaccurate BG monitoring systems bear the risk of false treatment decisions by the diabetes patient and subsequent possible severe health injury, manufacturers should regularly and effectively check the quality of BG meters and BG test strips.

System Accuracy Evaluation of 43 Blood Glucose Monitoring Systems for Self-Monitoring of Blood Glucose according to DIN EN ISO 15197

Background: The accuracy of systems for self-monitoring of blood glucose is important, as reliable measurement results are a prerequisite for therapeutic decisions. Methods: This system accuracy evaluation study was performed according to DIN EN ISO 15197:2003 for 43 Conformité Européenne (CE)-labeled blood glucose (BG) monitoring systems. Measurement results of each system were compared with results of the designated comparison method (manufacturers measurement procedure): glucose oxidase method (YSI 2300 glucose analyzer) or hexokinase method (Hitachi 917/ cobas 501). Results: Complete assessment according to the International Organization for Standardization (ISO) standard was performed for 34 out of 43 systems, and 27 (79.4%) meet the requirements of the standard, i.e., ≥95% of their results showed at least the minimum acceptable accuracy. For 9 of the 43 systems, complete accuracy assessment was not performed due to an oxygen sensitivity (manufacturers labeling). The bias (according to Bland and Altman) of all 43 evaluated systems ranged from −14.1% to +12.4%. Conclusions: From the 34 systems completely assessed, 7 systems did not fulfill the minimal accuracy requirements of the ISO standard. The CE mark apparently does not guarantee that all BG systems provide accuracy according to the standard. Because inaccurate systems bear the risk of false therapeutic decisions, regular and standardized evaluation of BG meters and test strips should be requested in order to ensure adherence to quality standards.

Lot-to-Lot Variability of Test Strips and Accuracy Assessment of Systems for Self-Monitoring of Blood Glucose according to ISO 15197

Background: Accurate and reliable blood glucose (BG) measurements require that different test strip lots of the same BG monitoring system provide comparable measurement results. Only a small number of studies addressing this question have been published. Methods: In this study, four test strip lots for each of five different BG systems [Accu-Chek® Aviva (system A), FreeStyle Lite® (system B), GlucoCheck XL (system C), Pura™/mylife™ Pura (system D), and OneTouch® Verio ™ Pro (system E)] were evaluated with procedures according to DIN EN ISO 15197:2003. The BG system measurement results were compared with the manufacturers measurement procedure (glucose oxidase or hexokinase method). Relative bias according to Bland and Altman and system accuracy according to ISO 15197 were analyzed. A BG system consists of the BG meter itself and the test strips. Results: The maximum lot-to-lot difference between any two of the four evaluated test strip lots per BG system was 1.0% for system E, 2.1% for system A, 3.1% for system C, 6.9% for system B, and 13.0% for system D. Only two systems (systems A and B) fulfill the criteria of DIN EN ISO 15197:2003 with each test strip lot. Conclusions: Considerable lot-to-lot variability between test strip lots of the same BG system was found. These variations add to other sources of inaccuracy with the specific BG system. Manufacturers should regularly and effectively check the accuracy of their BG meters and test strips even between different test strip lots to minimize risk of false treatment decisions.

Continuous Glucose Profiles in Healthy Subjects under Everyday Life Conditions and after Different Meals

Background: This study investigated continuous glucose profiles in nondiabetic subjects. Methods: Continuous interstitial glucose measurement was performed under everyday life conditions (2 days) and after ingestion of four meals with standardized carbohydrate content (50 grams), but with different types of carbohydrates and variable protein and fat content. Twenty-four healthy volunteers (12 female, 12 male, age 27.1 ± 3.6 years) participated in the study. Each subject wore two microdialysis devices (SCGM1, Roche Diagnostics) simultaneously. Results: The mean 24-hour interstitial glucose concentration under everyday life conditions was 89.3 ± 6.2 mg/dl (mean ± SD, n = 21), and mean interstitial glucose concentrations at daytime and during the night were 93.0 ± 7.0 and 81.8 ± 6.3 mg/dl, respectively. The highest postprandial glucose concentrations were observed after breakfast: 132.3 ± 16.7 mg/dl (range 101–168 mg/dl); peak concentrations after lunch and dinner were 118.2 ± 13.4 and 123.0 ± 16.9 mg/dl, respectively. Mean time to peak glucose concentration was between 46 and 50 minutes. After ingestion of standardized meals with fast absorption characteristics, peak interstitial glucose concentrations were 133.2 ± 14.4 and 137.2 ± 21.1 mg/dl, respectively. Meals with a higher fiber, protein, and fat content induced a smaller increase and a slower decrease of postprandial glucose concentrations with peak values of 99.2 ± 10.5 and 122.1 ± 20.4 mg/dl, respectively. Conclusions: This study provided continuous glucose profiles in nondiabetic subjects and demonstrated that differences in meal composition are reflected in postprandial interstitial glucose concentrations. Regarding the increasing application of continuous glucose monitoring in diabetic patients, these data suggest that detailed information about the ingested meals is important for adequate interpretation of postprandial glucose profiles.

Xp-duplications with and without sex reversal

Duplications in Xp including the DSS (dosage sensitive sex reversal) region cause male to female sex reversal. We investigated two patients from families with Xp duplications. The first case was one of two sisters with karyotype 46,XY, der(22), t(X;22)(p11.3;p11)mat and unambiguous female genitalia. The living sister was developmentally retarded, and showed multiple dysmorphic features and an acrocallosal syndrome. The second case was a boy with a maternally inherited direct duplication of Xp21.3-pter with the breakpoint close to the DSS locus. He had multiple abnormalities and micropenis, but otherwise unambiguous male genitalia. We performed quantitative Southern blot analysis with probes from Xp22.13 to p21.2 to define the duplicated region. Clinical, cytogenetic, and molecular data from both patients were compared with those of previously reported related cases. A comparison of the extragenital symptoms revealed no differences between patients with or without sex reversal. In both cases, the symptoms were non-specific. Among 22 patients with a duplication in Xp, nine had unambiguous female genitalia and a well-documented duplication of the DSS region. Two patients with duplication of DSS showed ambiguous external genitalia. From these data, we conclude that induction of testicular tissue may start in these patients, but that the type of genitalia depends on the degree of subsequent degeneration by a gene in DSS.

Ellobius lutescens: sex determination and sex chromosome.

The mole vole Ellobius lutescens is an interesting animal, not only concerning its sex determination mechanism without the Y-chromosomal Sry gene, that triggers sex determination in nearly all other mammalian species, but also regarding the karyotype with an odd number of chromosomes, being identical in male and female animals. The odd chromosome represents the X chromosome, and therefore, even males do not have a Y chromosome. We present an overview of a search for candidate genes of male sex determination in the mole vole Ellobius lutescens. A singular X raises questions about the need for X chromosome inactivation in female cells. We present preliminary data that support a hypothesis that the E. lutescensXist gene may be degenerated and thus non-functional.

System Accuracy Evaluation of Four Systems for Self-Monitoring of Blood Glucose Following ISO 15197 Using a Glucose Oxidase and a Hexokinase-Based Comparison Method

Background: The standard ISO (International Organization for Standardization) 15197 is widely accepted for the accuracy evaluation of systems for self-monitoring of blood glucose (SMBG). Accuracy evaluation was performed for 4 SMBG systems (Accu-Chek® Aviva, Contour®XT, GlucoCheck XL, GlucoMen® LX PLUS) with 3 test strip lots each. To investigate a possible impact of the comparison method on system accuracy data, 2 different established methods were used. Methods: The evaluation was performed in a standardized manner following test procedures described in ISO 15197:2003 (section 7.3). System accuracy was assessed by applying ISO 15197:2003 and in addition ISO 15197:2013 criteria (section 6.3.3). For each system, comparison measurements were performed with a glucose oxidase (YSI 2300 STAT Plus™ glucose analyzer) and a hexokinase (cobas® c111) method. Results: All 4 systems fulfilled the accuracy requirements of ISO 15197:2003 with the tested lots. More stringent accuracy criteria of ISO 15197:2013 were fulfilled by 3 systems (Accu-Chek Aviva, ContourXT, GlucoMen LX PLUS) when compared to the manufacturer’s comparison method and by 2 systems (Accu-Chek Aviva, ContourXT) when compared to the alternative comparison method. All systems showed lot-to-lot variability to a certain degree; 2 systems (Accu-Chek Aviva, ContourXT), however, showed only minimal differences in relative bias between the 3 evaluated lots. Conclusions: In this study, all 4 systems complied with the evaluated test strip lots with accuracy criteria of ISO 15197:2003. Applying ISO 15197:2013 accuracy limits, differences in the accuracy of the tested systems were observed, also demonstrating that the applied comparison method/system and the lot-to-lot variability can have a decisive influence on accuracy data obtained for a SMBG system.

Characterization of Pisrt1/Foxl2 in Ellobius lutescens and exclusion as sex-determining genes.

The rodent Ellobius lutescens is an exceptional mammal which determines male sex constitutively without the SRY gene and, therefore, may serve as an animal model for human 46,XX female-to-male sex reversal. It was suggested that other factors of the network of sex-determining genes determine maleness in these animals. However, some sex-determining genes like SOX9 and SF1 have already been excluded by segregation analysis as primary sex-determining factors in E. lutescens. In this work, we have cloned and characterized two genes of the PIS (polled intersex syndrome) gene interval, which were reported as candidates in female-to-male sex reversal in hornless goats recently. The genes Foxl2 and Pisrt1 from that interval were identified in E. lutescens DNA and mapped to Chromosome 8. We have excluded linkage of Foxl2 and Pisrt1 loci with the sex of the animals. Hence, the involvement of this gene region in sex determination may be specific for goats and is not a general mechanism of XX sex reversal or XX male sex determination.

Partial Pressure of Oxygen in Capillary Blood Samples from the Fingertip

Many people with diabetes routinely measure their blood glucose (BG) on capillary blood samples from the fingertip. Beside other interfering factors, the blood samples’ partial pressure of oxygen (pO2) can affect BG measurements, particularly in systems based on glucose oxidase (GOx) enzyme reactions on test strips.1,2 Indeed, many of the available home-use systems for self-monitoring of blood glucose (SMBG) utilize the GOx enzyme reaction, which is prone to oxygen interference; however, in the literature, poor information is available concerning physiological pO2 values and possible variations in capillary blood from the fingertip in people with diabetes. In this investigation, the pO2 of capillary blood samples obtained from fingertips was determined in 110 subjects (55 female, 31 with type 1 diabetes mellitus, 69 with type 2 diabetes mellitus, 10 without diabetes; mean age 61 years, from 19 to 78 years); most of them were expected to perform SMBG regularly. The subjects had no acute serious diseases. They participate regularly in SMBG system evaluation studies at the Institute for Diabetes-Technology GmbH at Ulm University, Ulm, Germany. The study protocol was approved by the Ulm University Ethics Committee. Capillary blood samples were obtained by skin puncture, and the pO2 was analyzed on a blood gas analyzer (OPTI™ CCA-TS Analysator, OPTI Medical System Inc., Roswell, GA). Maintenance, handling, and quality control of the blood gas analyzer were performed according to the manufacturer’s labeling. Regular internal and external quality control measurements were performed, as required by German national guidelines. Sample collection and pO2 measurements were performed by trained clinical personnel. The 110 subjects showed a mean pO2 of 71.1 mmHg (standard deviation ± 6.9 mmHg), ranging from 49 to 86 mmHg. Female and male subjects showed similar mean pO2 values (72.5 and 69.8 mmHg, respectively). Ninety-four subjects (~85%) showed pO2 values between >60 and ≤80 mmHg, 6 subjects (~5%) showed pO2 values ≤60 mmHg, and 10 subjects (~9%) showed pO2 values >80 mmHg (Figure 1). Lowest pO2 values (53 and 49 mmHg) were found in two subjects with stable chronic respiratory disease. Figure 1. Relative number of subjects with pO2 values within the respective category. Our results indicate that a broad range of capillary pO2 values occur among a population of healthy people and people with diabetes without acute serious diseases. In a previous study using venous blood samples adjusted to different pO2 levels, we observed remarkable measurement deviations with some GOx systems. Particularly at pO2 ≤45 mmHg, we found considerably overestimated measurements.2 Decreased pO2 values can occur in patients with respiratory diseases, such as chronic obstructive pulmonary disease,3 which is described as being associated with type 2 diabetes.4 At high altitudes or also during long-distance flights, up to ~40% decreased pO2 is reported for arterial blood samples;5 a similar behavior can also be expected for capillary blood samples from the fingertip. In conditions with decreased pO2 values in capillary blood, measurements with oxygen-sensitive systems could be affected, and hypoglycemic events might not be detected adequately. Further investigations should be performed focusing on pO2 variations in capillary blood from fingertips in people with diabetes and the possible impact on glucose measurement results obtained with oxygen-sensitive systems.

Analytical Performance Requirements for Systems for Self-Monitoring of Blood Glucose With Focus on System Accuracy: Relevant Differences Among ISO 15197:2003, ISO 15197:2013, and Current FDA Recommendations.

In the European Union (EU), the ISO (International Organization for Standardization) 15197 standard is applicable for the evaluation of systems for self-monitoring of blood glucose (SMBG) before the market approval. In 2013, a revised version of this standard was published. Relevant revisions in the analytical performance requirements are the inclusion of the evaluation of influence quantities, for example, hematocrit, and some changes in the testing procedures for measurement precision and system accuracy evaluation, for example, number of test strip lots. Regarding system accuracy evaluation, the most important change is the inclusion of more stringent accuracy criteria. In 2014, the Food and Drug Administration (FDA) in the United States published their own guidance document for the premarket evaluation of SMBG systems with even more stringent system accuracy criteria than stipulated by ISO 15197:2013. The establishment of strict accuracy criteria applicable for the premarket evaluation is a possible approach to further improve the measurement quality of SMBG systems. However, the system accuracy testing procedure is quite complex, and some critical aspects, for example, systematic measurement difference between the reference measurement procedure and a higher-order procedure, may potentially limit the apparent accuracy of a given system. Therefore, the implementation of a harmonized reference measurement procedure for which traceability to standards of higher order is verified through an unbroken, documented chain of calibrations is desirable. In addition, the establishment of regular and standardized post-marketing evaluations of distributed test strip lots should be considered as an approach toward an improved measurement quality of available SMBG systems.