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1.  Analysis of an Electrochemical Blood Glucose Monitoring System with Hematocrit Compensation: Improved Accuracy by Design 
The article entitled “Hematocrit Compensation in Electrochemical Blood Glucose Monitoring Systems” by Teodorczyk and colleagues in this issue of Journal of Diabetes Science and Technology demonstrates that the OneTouch® Verio™ glucose meter meets current regulatory expectations for glucose meter performance and is relatively free from interference by hematocrit. The lack of influence of hematocrit on whole blood glucose results is a valuable attribute for hospital applications, where greater variation of hematocrit among patients is anticipated. The choice of reference method for evaluation of glucose meters is an important consideration, and it is not clear to what extent reference methods used to evaluate glucose meters are also free from hematocrit interferences.
PMCID: PMC3440038  PMID: 22768897
glucose meter; hematocrit; reference method
2.  The All Our Babies pregnancy cohort: design, methods, and participant characteristics 
BMC Pregnancy and Childbirth  2013;13(Suppl 1):S2.
The prospective cohort study design is ideal for examining diseases of public health importance, as its inherent temporal nature renders it advantageous for studying early life influences on health outcomes and research questions of aetiological significance. This paper will describe the development and characteristics of the All Our Babies (AOB) study, a prospective pregnancy cohort in Calgary, Alberta, Canada designed to examine determinants of maternal, infant, and child outcomes and identify barriers and facilitators in health care utilization.
Women were recruited from health care offices, communities, and through Calgary Laboratory Services before 25 weeks gestation from May 2008 to December 2010. Participants completed two questionnaires during pregnancy, a third at 4 months postpartum, and are currently being followed-up with questionnaires at 12, 24, and 36 months. Data was collected on pregnancy history, demographics, lifestyle, health care utilization, physical and mental health, parenting, and child developmental outcomes and milestones. In addition, biological/serological and genetic markers can be extracted from collected maternal and cord blood samples.
A total of 4011 pregnant women were eligible for recruitment into the AOB study. Of this, 3388 women completed at least one survey. The majority of participants were less than 35 years of age, Caucasian, Canadian born, married or in a common-law relationship, well-educated, and reported household incomes above the Calgary median. Women who discontinued after the first survey (n=123) were typically younger, non-Caucasian, foreign-born, had lower education and household income levels, were less likely to be married or in a common-law relationship, and had poor psychosocial health in early pregnancy. In general, AOB participants reflect the pregnant and parenting population at local and provincial levels, and perinatal indicators from the study are comparable to perinatal surveillance data.
The extensive and rich data collected in the AOB cohort provides the opportunity to answer complex questions about the relationships between biology, early experiences, and developmental outcomes. This cohort will contribute to the understanding of the biologic mechanisms and social/environmental pathways underlying associations between early and later life outcomes, gene-environment interactions, and developmental trajectories among children.
PMCID: PMC3561154  PMID: 23445747
3.  Pharmacokinetic analysis of topical tobramycin in equine tears by automated immunoassay 
Ophthalmic antibiotic therapy in large animals is often used empirically because of the lack of pharmacokinetics studies. The purpose of the study was to determine the pharmacokinetics of topical tobramycin 0.3% ophthalmic solution in the tears of normal horses using an automated immunoassay analysis.
The mean tobramycin concentrations in the tears at 5, 10, 15, 30 minutes and 1, 2, 4, 6 hours after administration were 759 (±414), 489 (±237), 346 (±227), 147 (±264), 27.6 (±28.4), 14.8 (±66.6), 6.7 (±18.6), and 23.4 (±73.4) mg/L. Mean tobramycin concentration was maintained above the MIC90 for commonly isolated bacteria for 68.5 min.
A single dose of topical tobramycin resulted in therapeutic concentrations of tobramycin in the tears for 1 h after administration. Therapeutic levels of tobramycin remained in equine tears 6 times longer than was reported in rabbit tears.
PMCID: PMC3489562  PMID: 22909398
Antibiotic; Equine; Pharmacokinetics; Tear; Tobramycin; Topical; Ophthalmology
4.  Basophil activation test compared to skin prick test and fluorescence enzyme immunoassay for aeroallergen-specific Immunoglobulin-E 
Skin prick test (SPT) and fluorescence enzyme immunoassay (FEIA) are widely used for the diagnosis of Immunoglobulin-E (IgE)-mediated allergic disease. Basophil activation test (BAT) could obviate disadvantages of SPT and FEIA. However, it is not known whether BAT gives similar results as SPT or FEIA for aeroallergens.
In this study, we compared the results of SPT, BAT and FEIA for different aeroallergens.
We performed BAT, SPT and FEIA in 41 atopic subjects (symptomatic and with positive SPT for at least 1 of 9 common aeroallergens) and 31 non-atopic subjects (asymptomatic and with negative SPT).
Correlations between SPT and BAT, SPT and FEIA, and BAT and FEIA results were statistically significant but imperfect. Using SPT as the "gold standard", BAT and FEIA were similar in sensitivity. However, BAT had lower specificity than FEIA. False positive (BATposSPTneg) results were frequent in those atopic subjects who were allergic by SPT to a different allergen and rare in non-atopic subjects. The false positivity in atopic subjects was due in part to high levels of serum Total-IgE (T-IgE) levels in atopic individuals that lead to basophil activation upon staining with fluorochrome-labeled anti-IgE.
As an alternative to SPT in persons allergic to aeroallergens, BAT in its present form is useful for distinguishing atopic from non-atopic persons. However, BAT in its present form is less specific than FEIA when determining the allergen which a patient is allergic to. This is due to IgE staining-induced activation of atopic person's basophils and/or nonspecific hyperreactivity of atopic person's basophils.
PMCID: PMC3398323  PMID: 22264407
Allergic disease; Basophil activation test; Fluorescence enzyme immunoassay; Skin prick test; Aeroallergen; Immunoglobulin-E
5.  Analysis of the Performance of the CONTOUR® TS Blood Glucose Monitoring System: When Regulatory Performance Criteria Are Met, Should We Have Confidence to Use A Medical Device with All Patients? 
The article entitled, Performance of the CONTOUR® TS Blood Glucose Monitoring System, by Frank and colleagues in this issue of Journal of Diabetes Science and Technology, demonstrates that the CONTOUR® TS glucose meter exceeds current regulatory expectations for glucose meter performance. However, the appropriateness of current regulatory expectations, such as International Organization for Standardization (ISO) 15197:2003, is being reevaluated because of increasing concern regarding the reliability of glucose meters in ambulatory and hospitalized environments. Between 2004 and 2008, 12,673 serious adverse events with glucose meters that met the ISO 15197 expectations were reported in the Food and Drug Administration–Manufacturer and User Facility Device Experience surveillance database. Should different glucose meter performance criteria be applied to ambulatory versus critical care patients?
PMCID: PMC3045223  PMID: 21303646
assisted-monitoring blood glucose devices; ISO 15197:2003 accuracy performance expectations; MAUDE surveillance system database; self-monitoring blood glucose devices
6.  Estimates of Total Analytical Error in Consumer and Hospital Glucose Meters Contributed by Hematocrit, Maltose, and Ascorbate 
Patients and physicians expect accurate whole blood glucose monitoring even when patients are anemic, are undergoing peritoneal dialysis, or have slightly elevated ascorbate levels. The objective of this study was to estimate analytical error in two consumer and two hospital glucose meters contributed by variations in hematocrit, maltose, ascorbate, and imprecision.
The influence of hematocrit (20–60%), maltose, and ascorbate were tested alone and in combination with each glucose meter and with a reference plasma glucose method at three concentrations of glucose. Precision was determined by consecutive analysis (n = 20) at three levels of glucose. Multivariate regression analysis was used to estimate the bias associated with the interferences, alone and in combination. Total analytical error was estimated as |% bias| + 1.96 (% imprecision).
Three meters demonstrated hematocrit bias that was dependent upon glucose concentration. Maltose had profound concentration-dependent positive bias on the consumer meters, and the extent of maltose bias was dependent on hematocrit. Ascorbate produced small but statistically significant biases on three meters. Coincident low hematocrit, presence of maltose, and presence of ascorbate increased the observed bias and was summarized by estimation of total analytical error. Among the four glucose meter devices assessed, estimates of total analytical error in glucose measurement ranged from 6 to 68% under the conditions tested.
The susceptibility of glucose meters to clinically significant analytical biases is highly device-dependent, and low hematocrit exacerbated the observed analytical error.
PMCID: PMC3005060  PMID: 21129345
ascorbate; bias; glucose meters; hematocrit; imprecision; interference; maltose; total error
7.  Cord blood calcium, phosphate, magnesium, and alkaline phosphatase gestational age-specific reference intervals for preterm infants 
BMC Pediatrics  2011;11:76.
The objective was to determine the influence of gestational age, maternal, and neonatal variables on reference intervals for cord blood bone minerals (calcium, phosphate, magnesium) and related laboratory tests (alkaline phosphatase, and albumin-adjusted calcium), and to develop gestational age specific reference intervals based on infants without influential pathological conditions.
Cross-sectional study. 702 babies were identified as candidates for this study in a regional referral neonatal unit. After exclusions (for anomalies, asphyxia, maternal magnesium sulfate administration, and death), relationships were examined between cord blood serum laboratory analytes (calcium, phosphate, magnesium, alkaline phosphatase, and albumin-adjusted calcium) with gestation age and also with maternal and neonatal variables using multiple linear regression. Infants with influential pathological conditions were omitted from the development of gestational age specific reference intervals for the following categories: 23-27, 28-31, 32-34, 35-36 and > 36 weeks.
Among the 506 preterm and 54 terms infants included in the sample. Phosphate, magnesium, and alkaline phosphatase in cord blood serum decreased with gestational age, calcium increased with gestational age. Those who were triplets, small for gestational age, and those whose mother had pregnancy-induced hypertension were influential for most of the analytes. The reference ranges for the preterm infants ≥ 36 weeks were: phosphate 1.5 to 2.6 mmol/L (4.5 to 8.0 mg/dL), calcium: 2.1 to 3.1 mmol/L (8.3 to 12.4 mg/dL); albumin-adjusted calcium: 2.3 to 3.2 mmol/L (9.1 to 12.9 mg/dL); magnesium 0.6 to 1.0 mmol/L (1.4 to 2.3 mg/dL), and alkaline phosphatase 60 to 301 units/L.
These data suggest that gestational age, as well as potentially pathogenic maternal and neonatal variables should be considered in the development of reference intervals for preterm infants.
PMCID: PMC3179922  PMID: 21884590
Infant; premature; Infant; very low birth weight; reference values; reference ranges
8.  Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill's epidemiologic criteria for causality 
Nutrition Journal  2011;10:41.
Modern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hill's criteria.
Systematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone-related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined.
Fifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine calcium excretion, calcium balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine calcium excretion rates were consistent with osteoporosis development; however calcium balance studies did not demonstrate loss of whole body calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis.
A causal association between dietary acid load and osteoporotic bone disease is not supported by evidence and there is no evidence that an alkaline diet is protective of bone health.
PMCID: PMC3114717  PMID: 21529374
9.  All Our Babies Cohort Study: recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment 
Preterm birth is the leading cause of perinatal morbidity and mortality. Risk factors for preterm birth include a personal or familial history of preterm delivery, ethnicity and low socioeconomic status yet the ability to predict preterm delivery before the onset of preterm labour evades clinical practice. Evidence suggests that genetics may play a role in the multi-factorial pathophysiology of preterm birth. The All Our Babies Study is an on-going community based longitudinal cohort study that was designed to establish a cohort of women to investigate how a women's genetics and environment contribute to the pathophysiology of preterm birth. Specifically this study will examine the predictive potential of maternal leukocytes for predicting preterm birth in non-labouring women through the examination of gene expression profiles and gene-environment interactions.
Collaborations have been established between clinical lab services, the provincial health service provider and researchers to create an interdisciplinary study design for the All Our Babies Study. A birth cohort of 2000 women has been established to address this research question. Women provide informed consent for blood sample collection, linkage to medical records and complete questionnaires related to prenatal health, service utilization, social support, emotional and physical health, demographics, and breast and infant feeding. Maternal blood samples are collected in PAXgene™ RNA tubes between 18-22 and 28-32 weeks gestation for transcriptomic analyses.
The All Our Babies Study is an example of how investment in clinical-academic-community partnerships can improve research efficiency and accelerate the recruitment and data collection phases of a study. Establishing these partnerships during the study design phase and maintaining these relationships through the duration of the study provides the unique opportunity to investigate the multi-causal factors of preterm birth. The overall All Our Babies Study results can potentially lead to healthier pregnancies, mothers, infants and children.
PMCID: PMC3022739  PMID: 21192811
10.  Seasonal Variation in Hemoglobin A1c: Is It the Same in Both Hemispheres? 
There are several reports from locations in the northern hemisphere of seasonal variation in hemoglobin A1c (HbA1c) levels with higher values noted in the cooler months. The variation has been attributed to holiday seasons, temperature differences, and changes in diet. This article describes the seasonal variation in both hemispheres and in a country on the equator with minimal temperature variation.
The mean and median HbA1c by month was calculated for a maximum of 2 years for HbA1c data from the different locations: Edmonton and Calgary, Canada; Singapore; Melbourne, Australia; and Marshfield, Wisconsin. The mean monthly temperature for each location was found from available meteorological information.
In both northern and southern hemispheres, the HbA1c was higher in cooler months and lower in the warmer months. In Singapore, where there is minimal temperature variation, there is also minimal variation in HbA1c values over the year. The difference in HbA1c over a year appears to be related to the difference in temperature.
Hemoglobin A1c is higher in cooler months and lower in the warmer months in both hemispheres. In a country with minimal monthly temperature variation, there is only minimal variation in HbA1c values through the year. In all locations, the mean and median HbA1c declined over the study period, possibly due to better glycemic control of patients with diabetes or an increase in use of HbA1c as a screening test for diabetes or a combination of both.
PMCID: PMC2769947  PMID: 20144310
hemoglobin A1c; seasonal; variation
11.  Low urine pH and acid excretion do not predict bone fractures or the loss of bone mineral density: a prospective cohort study 
The acid-ash hypothesis, the alkaline diet, and related products are marketed to the general public. Websites, lay literature, and direct mail marketing encourage people to measure their urine pH to assess their health status and their risk of osteoporosis.
The objectives of this study were to determine whether 1) low urine pH, or 2) acid excretion in urine [sulfate + chloride + 1.8x phosphate + organic acids] minus [sodium + potassium + 2x calcium + 2x magnesium mEq] in fasting morning urine predict: a) fragility fractures; and b) five-year change of bone mineral density (BMD) in adults.
Design: Cohort study: the prospective population-based Canadian Multicentre Osteoporosis Study. Multiple logistic regression was used to examine associations between acid excretion (urine pH and urine acid excretion) in fasting morning with the incidence of fractures (6804 person years). Multiple linear regression was used to examine associations between acid excretion with changes in BMD over 5-years at three sites: lumbar spine, femoral neck, and total hip (n = 651). Potential confounders controlled included: age, gender, family history of osteoporosis, physical activity, smoking, calcium intake, vitamin D status, estrogen status, medications, renal function, urine creatinine, body mass index, and change of body mass index.
There were no associations between either urine pH or acid excretion and either the incidence of fractures or change of BMD after adjustment for confounders.
Urine pH and urine acid excretion do not predict osteoporosis risk.
PMCID: PMC2890599  PMID: 20459740
12.  Use of Serial Patient Hemoglobin A1c Differences to Determine Long-Term Imprecision of Immunoassay and High-Performance Liquid Chromatography Analyzers 
The quality of the HbA1c assay is inversely proportional to the variation of the assay. Most published measures of HbA1c variation are limited by the data collection period, the statistical treatment of outliers, and even the noncommutability of the products used to generate the variation measurements. We have used an alternate approach to derive HbA1c variation, using serial patient data.
HbA1c measurements of outpatient blood sample pairs drawn within 30 days of each other were made on three different immunoassay systems: the Roche INTEGRA® 700, the Roche INTEGRA® 400, and the Dade Dimension® RxL; and two high-performance liquid chromatography assays: the Tosoh G7 and the Tosoh 2.2+. The standard deviation of duplicates was calculated for the following time intervals: 1 to 3 days, 4 to 6 days, 7 to 9 days,…, 28 to 30 days. These intra-individual variations were then plotted; extrapolation to time zero yields the long term total random error which consists of both analytic and pre-analytic error. Data collection periods were usually 2 years.
At the mean HbA1cs of 7.08%, 7.14%, 7.20%, 6.96%, and 7.51% for populations tested on the Roche INTEGRA 700, Roche INTEGRA 400, Dade Dimension RxL, Tosoh 2.2+, and Tosoh G7, respectively, the total analytic imprecisions (coefficient of variation) were 2.56%, 2.29%, 2.25%, 1.66%, and 1.14%, respectively.
Assessment of the HbA1c long term total imprecisions shows that while the three immunoassay systems are acceptable, the Tosoh HbA1c analyzers demonstrate superior analytic performance.
PMCID: PMC2769869  PMID: 20144278
hemoglobin A1c; long-term analytic variation
13.  Variation in the Frequency of Hemoglobin A1c (HbA1c) Testing: Population Studies Used to Assess Compliance with Clinical Practice Guidelines and Use of HbA1c to Screen for Diabetes 
The volume of hemoglobin A1c (HbA1c) testing has increased dramatically over the past decade and few studies have attempted to determine how the test is used. The goals of this study were to evaluate the frequency of HbA1c testing in regional populations to assess the extent of screening for diabetes and to determine if the HbA1c testing intervals of known diabetic patients were consistent with clinical practice guidelines.
Two years of HbA1c results were extracted from laboratory information systems in four regions of the province of Alberta that represent urban, mixed urban–rural, and rural populations. HbA1c testing frequencies and the proportions of nondiabetic patients undergoing HbA1c tests were derived.
Approximately 60% of HbA1c tests in each region were done on patients who had only a single test during the 2-year interval. Testing of nondiabetic patients accounted for 24% of HbA1c tests and varied by region. While the cumulative frequency distributions of HbA1c test intervals resembled each other, detailed analyses of the frequency distributions depicted broad multimodal peaks and regional variations that suggest a great deal of heterogeneity among practices. The most common HbA1c testing interval was 3 months ± 3 weeks in each region and is consistent with the 3-month test interval target in a clinical practice guideline.
HbA1c testing is being performed on a substantial proportion of nondiabetic patients. On average, patients with diabetes in Alberta receive 1.5 HbA1c tests per year. However, we observed regional differences in the frequency of testing and variation in compliance with clinical practice guidelines.
PMCID: PMC2769871  PMID: 20144276
diabetes mellitus–blood; diabetes mellitus–diagnosis; glycated hemoglobins; screening; utilization
14.  Phosphate decreases urine calcium and increases calcium balance: A meta-analysis of the osteoporosis acid-ash diet hypothesis 
Nutrition Journal  2009;8:41.
The acid-ash hypothesis posits that increased excretion of "acidic" ions derived from the diet, such as phosphate, contributes to net acidic ion excretion, urine calcium excretion, demineralization of bone, and osteoporosis. The public is advised by various media to follow an alkaline diet to lower their acidic ion intakes. The objectives of this meta-analysis were to quantify the contribution of phosphate to bone loss in healthy adult subjects; specifically, a) to assess the effect of supplemental dietary phosphate on urine calcium, calcium balance, and markers of bone metabolism; and to assess whether these affects are altered by the b) level of calcium intake, c) the degree of protonation of the phosphate.
Literature was identified through computerized searches regarding phosphate with surrogate and/or direct markers of bone health, and was assessed for methodological quality. Multiple linear regression analyses, weighted for sample size, were used to combine the study results. Tests of interaction included stratification by calcium intake and degree of protonation of the phosphate supplement.
Twelve studies including 30 intervention arms manipulated 269 subjects' phosphate intakes. Three studies reported net acid excretion. All of the meta-analyses demonstrated significant decreases in urine calcium excretion in response to phosphate supplements whether the calcium intake was high or low, regardless of the degree of protonation of the phosphate supplement. None of the meta-analyses revealed lower calcium balance in response to increased phosphate intakes, whether the calcium intake was high or low, or the composition of the phosphate supplement.
All of the findings from this meta-analysis were contrary to the acid ash hypothesis. Higher phosphate intakes were associated with decreased urine calcium and increased calcium retention. This meta-analysis did not find evidence that phosphate intake contributes to demineralization of bone or to bone calcium excretion in the urine. Dietary advice that dairy products, meats, and grains are detrimental to bone health due to "acidic" phosphate content needs reassessment. There is no evidence that higher phosphate intakes are detrimental to bone health.
PMCID: PMC2761938  PMID: 19754972
15.  Derivation and internal validation of an equation for albumin-adjusted calcium 
Previously published equations to adjust calcium for albumin concentration may vary depending on factors such as the type of reagents used. Albumin-adjusted calcium equations derived from laboratories using the bromocresol purple (BCP) albumin binding reagent have not been described.
The linear regression equation for the binding of calcium and BCP-albumin was derived in a cohort of 4613 outpatients, and the albumin-adjusted calcium equation was internally validated in a separate cohort of 1538 subjects. The performance of this equation was compared with a previously published equation (adjusted [Ca](mmol/L) = total [Ca](mmol/L) + 0.02 (40 - [albumin] (g/L)) in 343 subjects with albumin < 33 g/L (below reference range).
The local adjustment equation was expressed by the relationship; adjusted [Ca](mmol/L) = total [Ca](mmol/L) + 0.012 (39.9 - [albumin](g/L)). The equation showed evidence of good internal validity (shrinkage value of adjusted r2 = -0.0059). Classification of calcium status differed between the two equations in 47 of 343 subjects with low serum albumin (weighted κ = 0.46; moderate agreement).
A locally derived and internally validated albumin-adjusted calcium equation differed from previously published equations and resulted in important differences in classification of calcium status in hypoalbuminemia patients. Individual laboratories should determine their own linear regression equation for calcium on albumin rather than relying on published formulas.
PMCID: PMC2607282  PMID: 19038049

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