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Objectives: To assess the effectiveness of interventions by laboratories and to increase rational and reduce unnecessary family physician test ordering., Design and Methods: MEDLINE [1946-present], EMBASE [1980-present], EBM Reviews [1991-present](Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects, - Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment, NHS Economic Evaluation Database), PubMed [1966-present], PubMed Central [1900-present], Scopus [1960-present], Web of Science [1900-present] and CINAHL [1982-present] were searched with no language or publication limits. Non-randomised studies were assessed with the Newcastle-Ottawa scale., Results: The search identified 9282 titles and abstracts, 238 were read in full-text and 3 cohort and 7 before- and after-studies were included. Most focused on changing a few tests and evaluated the interventions over several months. Seven changed laboratory forms (the two largest involved 5.2 million and 3.2 million tests), one negotiated a test ordering protocol with family physicians, and two required laboratory approval. They achieved an average 35% reduction in the 19 targeted tests, with a wide range (0%-100% reduction)., Conclusions: Ten studies were identified which tested interventions by laboratories to reduce test ordering by family physicians, and achieved an average 35% reduction in the 19 targeted tests. The rationale for choosing specific tests for intervention was often not explained, most studies targeted a few tests for several months, the tests and test volumes differed widely across studies, no author improved the results of previous interventions or asked participants their opinions about the intervention or assessed factors impeding change., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Context: Community-based programs are a common way of promoting colorectal cancer screening by primary care physicians. Fecal immunochemical testing (FIT) is a screening method commonly used in such programs. Fecal immunochemical testing has advantages to the patient as well as to clinical laboratories., Objective: To assess the operational test characteristics of a FIT pilot program in Calgary, Alberta, Canada, between April 2011 and May 2012., Design: Four hundred fifty-seven high-risk patients undergoing both FIT and colonoscopy were included. Areas under the curve and positive predictive values were derived for FIT values and biopsy-proven neoplasia. Subgroup analysis was also performed on men and women and for ages older and younger than the mean age of 62 years., Results: For colorectal carcinoma and colonic adenomas the areas under the curve were 0.79 (95% confidence interval 0.71-0.87) and 0.60 (95% confidence interval 0.54-0.65), respectively. The positive predictive value of a positive FIT result for any neoplasia was 53%. The overall performance of the test for all neoplasia was better for men and better for older individuals., Conclusions: The performance of FIT in this clinical setting was very good for detecting carcinoma, but marginal for detection of colonic adenomas.

Objectives: To identify inappropriate repeats of six common laboratory tests in a population sample of patients, using highly specific criteria based only on repeat time and test value., Methods: We used a laboratory informatics database to conduct a retrospective cohort study using a population sample of 103,000 patients in the city of Calgary with an index test in 2010 and uniform follow-up of 1 year. We examined six tests (cholesterol, hemoglobin A1c, thyroid-stimulating hormone, vitamin B12, vitamin D, and ferritin) with consensus-based or easily justified criteria for inappropriate repeats based solely on time to repeat and the index test value., Results: The percentages of tests repeated at 3, 6, and 12 months were 11%, 23%, and 41%, respectively. In total, 16% of these six tests were inappropriately repeated, representing an annual internal cost of $0.6 to $2.2 million Canadian dollars and corresponding to population-scaled national estimates for Canada and the United States of $160 million and $2.4 billion, respectively., Conclusions: Objective definitions based on repeated testing identified 16% of six studied tests as inappropriate, delineating a subset of inappropriate testing that is well suited to automated identification and intervention and that provides a likely lower bound on the true burden of inappropriate testing., (Copyright© by the American Society for Clinical Pathology.)

Objectives: Approaches to determining optimal locations for patient service centers (phlebotomy clinics) have not been addressed in the published literature. Using the city of Calgary, Alberta, Canada, as a test case, our objective is to present a novel method for determining underserviced geographic areas within a city to guide the choice of potential new patient service center locations., Methods: Data on travel distances for 198,883 phlebotomy visits as well as population data from the 2011 Canada Census were used for this study. Using geospatial mapping techniques, we produced maps of the city showing actual relative travel distances for patients as well as the geographic distribution of population density of patients undergoing phlebotomies., Results: There was a striking pattern of increased travel distances in certain parts of the city. These also corresponded to geographic areas with greater density of patients seeking phlebotomies., Conclusions: This analysis provided clear, objective evidence of communities that are currently relatively underserved by patient service centers. This approach could be used by other laboratories to plan the location of new patient service centers., (Copyright© by the American Society for Clinical Pathology.)

Background: Folate deficiency is rare in western countries and therefore blood tests for folate level have limited indications. One such indication is red cell macrocytosis, however it is unclear if the association of macrocytosis with folate deficiency is robust enough to serve as a risk marker. Our objective is to determine whether macrocytosis is a useful marker for folate deficiency., Findings: Paired data from the Calgary Laboratory Services Information System was analyzed using receiver operating characteristic (ROC) curves to determine strength of association between mean corpuscular volume and serum folate. Strength of association was analyzed for serum folate cut-off values of 12, 10, 8, and 6 nmol/L. Overall, 0.2% of individuals were folate deficient (<6 nmol/L serum folate). Based on ROC curves, at each cut-off level, mean corpuscular volume was a poor predictive marker for serum folate level., Conclusions: Folate deficiency is rare in Calgary, Alberta. Macrocytosis is not a strong predictor for folate deficiency.

Objectives: Very little is known about the relative contributions of physician specialty groups and individual physicians to overall clinical laboratory expenditures. The objectives of this study were to determine the costs of clinical laboratory test expenditures attributable to 30 medical specialties and the associated per capita physician expenditures for an entire major Canadian city. Only chemistry, hematology, and microbiology tests were included in this study., Methods: Retrospective cohort study involving all physicians in Calgary, Canada, and surrounding areas (n = 3,499) and secondary data on laboratory test orders., Results: Data were obtained on approximately 20 million test requests. The mean clinical laboratory test expenditure, in Canadian dollars, per physician was $27,945 for all physicians combined. Total expenditures by primary care physicians (family physicians and general practitioners) accounted for 58% of total expenditures., Conclusions: There was wide variation in clinical laboratory test expenditures among specialties and on a per capita basis within medical specialties., (Copyright© by the American Society for Clinical Pathology.)

This study provides an update on the incidence of chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) in a major Canadian city using the 2008 World Health Organization (WHO) diagnostic criteria. Incidence calculations were performed using data from a centralized flow cytometry laboratory servicing southern Alberta, Canada. The age-standardized incidence of 4.01 cases of CLL per 100,000 person-years is nearly half the rate previously reported in Canada. Compared to previous criteria based on absolute lymphocyte count rather than absolute B-cell count, utilizing the 2008 WHO criteria resulted in a 47.6% decline in CLL incidence (8.42 cases per 100,000 using 1996 criteria). As a consequence, MBL rates are 64% higher. In contrast to 1996 criteria showing a peak CLL incidence between ages 70-74, age-specific incidence rates show a continuous increase with advancing age using the 2008 guidelines. We also report a higher male to female ratio of CLL than previous Canadian reports (1.80:1). CLL incidence in southern Alberta is lower than rates recently reported in the United States using the same criteria. This difference may be due in part to the low median age and the lower proportion of persons of Caucasian European ancestry present in our study population., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Red blood cell (RBC) analysis is a key feature in the evaluation of hematological disorders. The gold standard light microscopy technique has high sensitivity, but is a relativity time-consuming and labor intensive procedure. This study tested the sensitivity and specificity of gold standard light microscopy manual differential to the CellaVision(®) DM96 (CCS; CellaVision, Lund, Sweden) automated image analysis system, which takes digital images of samples at high magnification and compares these images with an artificial neural network based on a database of cells and preclassified according to RBC morphology., Methods: In this study, 212 abnormal peripheral blood smears within the Calgary Laboratory Services network of hospital laboratories were selected and assessed for 15 different RBC morphologic abnormalities by manual microscopy. The same samples were reassessed as a manual addition from the instrument screen using the CellaVision(®) DM96 system with 8 microscope high power fields (×100 objective and a 22 mm ocular). The results of the investigation were then used to calculate the sensitivity and specificity of the CellaVision(®) DM96 system in reference to light microscopy., Results: The sensitivity ranged from a low of 33% (RBC agglutination) to a high of 100% (sickle cells, stomatocytes). The remainder of the RBC abnormalities tested somewhere between these two extremes. The specificity ranged from 84% (schistocytes) to 99.5% (sickle cells, stomatocytes)., Conclusions: Our results showed generally high specificities but variable sensitivities for RBC morphologic abnormalities.

Objectives: Community fecal immunochemical testing (FIT) screening programs are important for detecting early disease and can be effective when promoted by primary care physicians. Screening rates remain low across Canada and may be associated with sociodemographic factors., Design and Methods: Fecal immunochemical testing results for a new community-based screening program were obtained from Calgary Laboratory Services from November 18, 2013 to May 31, 2014. Screening rates were determined for specific age and sex cohorts and sociodemographic factors were inferred from census Canada data. Poisson regression and generalized estimating equations were used to test associations of screening rate with sociodemographic variables., Results: A total of 27,572 results were screened and included in our analysis. Recent immigrants (RR = 0.18, P = <.0001), Aboriginal First Nations (RR = 0.39, P = 0.01), Aboriginal Metis (RR = 0.14, P = 0.0003), visible minority Black (RR = 0.35, P = 0.0002), and higher education (RR = 0.65, P = <.0001) were associated with decreased screening. Visible minority Chinese (RR = 1.72, P = <.0001) were more likely to be screened. Household income was not associated with screening rate. Older individuals and females were less likely to be screened., Conclusion: There is significant geographic variation in screening rates in Calgary. These are associated with a number of sociodemographic factors., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

We sought to improve the diagnostic efficiency of flow cytometry investigation on blood by developing data-driven ordering guidelines. Our goal was to improve flow cytometry utilization by decreasing negative testing, therefore reducing healthcare costs. We investigated several laboratory tests performed alongside flow cytometry to identify biomarkers useful in excluding non-leukemic bloods. Test results and patient demographic features were subjected to receiver-operator characteristic (ROC) curve, logistic regression and classification tree analyses to find significant predictors and develop decision rules. Our data show that, in the absence of a compelling clinical indication, flow cytometry testing is largely non-informative on bloods from patients less than 50 years of age having an absolute lymphocyte count (ALC) below 5.0 × 10(9)/L. For patients over age 50 having an ALC below this value, a ferritin value above 450 μg/L is counter-indicative of B-cell clonality. Using these guidelines, 26% of cases were correctly predicted as negative with greater than 97% accuracy.

Objectives: There are conflicting recommendations regarding the use of prostate specific antigen (PSA) as a screening test. Integral to this debate is an understanding of who is currently being tested. The purpose of this study was to provide a detailed account of PSA testing practices in a major Canadian city (Calgary, Alberta) and to identify variables that may affect access to the PSA test., Design and Methods: PSA test counts were retrieved from Calgary Laboratory Services' Laboratory Information System from January 1, 2011 to December 31, 2011. A total of 75,914 individual PSA tests were included in our analysis. The frequency of PSA testing was plotted onto a dissemination area map of Calgary using ArcGIS software. Associations with sociodemographic variables were tested using Poisson regression., Results: The median PSA value was 0.93 μg/L and the median age at collection was 58 years. Forty-three percent of men aged 60-69 received a PSA test. Visible minority status 'Black' (P=0.0002) and Métis status (P=0.0075) were associated with lower PSA testing frequencies, while median household income (P=<0.0001) and university education (P=<0.0001) were associated with higher PSA testing frequencies., Conclusion: There are areas in Calgary which are significantly over or under tested relative to the mean. The amount of PSA testing in men <50 years of age is increasing, which is contrary to PSA testing guidelines., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

The emergence of massive datasets in a clinical setting presents both challenges and opportunities in data storage and analysis. This so called "big data" challenges traditional analytic tools and will increasingly require novel solutions adapted from other fields. Advances in information and communication technology present the most viable solutions to big data analysis in terms of efficiency and scalability. It is vital those big data solutions are multithreaded and that data access approaches be precisely tailored to large volumes of semi-structured/unstructured data. THE MAPREDUCE PROGRAMMING FRAMEWORK USES TWO TASKS COMMON IN FUNCTIONAL PROGRAMMING: Map and Reduce. MapReduce is a new parallel processing framework and Hadoop is its open-source implementation on a single computing node or on clusters. Compared with existing parallel processing paradigms (e.g. grid computing and graphical processing unit (GPU)), MapReduce and Hadoop have two advantages: 1) fault-tolerant storage resulting in reliable data processing by replicating the computing tasks, and cloning the data chunks on different computing nodes across the computing cluster; 2) high-throughput data processing via a batch processing framework and the Hadoop distributed file system (HDFS). Data are stored in the HDFS and made available to the slave nodes for computation. In this paper, we review the existing applications of the MapReduce programming framework and its implementation platform Hadoop in clinical big data and related medical health informatics fields. The usage of MapReduce and Hadoop on a distributed system represents a significant advance in clinical big data processing and utilization, and opens up new opportunities in the emerging era of big data analytics. The objective of this paper is to summarize the state-of-the-art efforts in clinical big data analytics and highlight what might be needed to enhance the outcomes of clinical big data analytics tools. This paper is concluded by summarizing the potential usage of the MapReduce programming framework and Hadoop platform to process huge volumes of clinical data in medical health informatics related fields.

Objective: The self-monitoring of blood glucose plays a critical role in management of diabetes mellitus. Although laboratory comparisons of glucose meter accuracy are often acceptable, clinical comparisons show frequent inaccuracies. In this paper, we evaluate the accuracy of self-monitoring blood glucose meters using glucose meter and serum comparisons from a large Canadian laboratory., Methods: This study was performed using secondary data obtained from the Laboratory Information System of Calgary Services, the sole provider of laboratory testing to Calgary and surrounding areas. We examined anonymous quality assurance data for glucose meter comparisons performed on home glucose meters between January 1, 2010, and April 30, 2013., Results: A total of 39 542 comparisons were recorded on 18 540 different subjects. Overall, 6.7% of differences were greater than the current International Standards Organization standard of 15%, and 3.7% exceeded the Canadian guideline of 20%., Conclusions: Glucose meter checks were infrequently performed (on average, once per 1.6 years). A significant subset of meter results was inaccurate., (Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Objective: To provide an update on the clinical usefulness of nonfasting versus fasting lipid testing to improve patient compliance, patient safety, and clinical assessment in cholesterol testing., Quality of Evidence: Recommendations are identified as supported by good, fair, and poor (conflicting or insufficient) evidence, according to the classifications adopted by the Canadian Task Force on Preventive Health Care., Main Message: Screening for dyslipidemia as a risk factor for coronary artery disease and management of lipid-lowering medications are key parts of primary care. Recent evidence has questioned the fasting requirement for lipid testing. In population-based studies, total cholesterol, high-density lipoprotein cholesterol, and non-low-density lipoprotein cholesterol all varied by an average of 2% with fasting status. For routine screening, nonfasting cholesterol measurement is now a reasonable alternative to a fasting cholesterol measurement. For patients with diabetes, the fasting requirement might be an important safety issue because of problems with hypoglycemia. For the monitoring of triglyceride and low-density lipoprotein cholesterol levels in patients taking lipid-lowering medications, fasting becomes more important., Conclusion: Fasting for routine lipid level determinations is largely unnecessary and unlikely to affect patient clinical risk stratification, while nonfasting measurement might improve patient compliance and safety., (Copyright© the College of Family Physicians of Canada.)

Background: Increasing laboratory test utilization is a major challenge facing clinical laboratories. However, in most instances we lack population level information on the patient groups to which increased testing is directed. Much recent work has been published on the sociodemographic correlates of 25-hydroxyvitamin D deficiency. An unanswered question, however, is whether testing is preferentially directed towards individuals with a higher likelihood of deficiency. In this paper we examine this question by combining laboratory information system data on testing rates with Census Canada data., Methods: We examined 1,436 census dissemination areas within the city of Calgary, Alberta, Canada. For each census dissemination area we determined age and sex-specific 25-hydroxyvitamin D testing rates over a one year period. We then compared these testing rates with the following sociodemographic variables obtained from Census Canada: first nations status, education level, household income, visible minority status, and recent immigrant status., Results: Overall, 6.9% of males in the city of Calgary were tested during the study period. Females were 1.7 times more likely to be tested than males. Testing rate increased with increasing age, with 16.8% of individuals 66 years and over tested during the one-year study period. Individuals having at least some university education were less likely to be tested (RR = 0.60; p < 0.0001). Interestingly, although visible minorities were over twice as likely to be tested as compared to non-visual minorities (RR = 2.25; p < 0.0001), recent immigrants, a group known to exhibit low 25 hydroxyvitamin D levels, were significantly less likely to be tested than non-recent immigrants (RR = 0.72; p = 0.0174). While median household income was modestly associated with increased testing (RR = 1.02; p < 0.0001), First Nations status and non-English speaking were not significant predictors of 25-hydroxyvitamin D testing., Conclusions: Testing for 25-hydroxyvitamin D is in part directed toward populations at higher risk of deficiency (visible minorities) and at higher risk of osteoporosis (older females), but a particularly high risk group (recent immigrants) is being tested at a lower rate than other patient groups.

Context: Many hematology laboratories have adopted semi-automated digital platforms for routine use and the evidence supporting their use is increasing., Aims: The CellaVision platforms are among the most thoroughly studied digital hematology platforms; we wished to determine the accuracy of CellaVision for reticulocyte counting., Design Materials and Methods: We compared reticulocyte counts performed manually, using the Beckman Coulter LH750 automated analyzer and with the CellaVision DM96 platform. We analyzed the results for pair-wise correlation and bias, and precision., Statistical Analyses Used: Analyses were performed using Statistical Package for the Social Sciences software (SPSS), including Spearman's rho correlation coefficient, Friedman's two-way Analysis Of Variance (ANOVA) for comparison of distributions; bias was compared by way of mean and standard deviation., Results: The CellaVision reticulocyte counts correlated most strongly with those of the analyzer (often considered the benchmark test); the reticulocyte count distributions were noted not to be significantly different from each other across all three methods. The mean and standard deviation of bias were lowest in the comparison of CellaVision and LH750 counts., Conclusions: Our data provide additional support for the accuracy of digital hematology applications using the CellaVision DM96 platform.

Objectives: The introduction of the Papanicolaou (Pap) test in Canada has led to a decline in both the incidence of, and mortality from, cervical cancer. However, cervical cancer in women under the age of 25 is rare, and the updated Canadian Task Force on Preventive Health Care recommendations advise against screening by Pap test in this age group. Screening under the age of 25 can lead to false-positive results or to treatment of lesions that may spontaneously regress. The purpose of this observational study was to determine how many Pap tests are performed in women less than 25 years of age despite current guidelines., Methods: Data were obtained from the Laboratory Information System of Calgary Laboratory Services for women under and over the age of 25 who underwent Pap testing between September and December 2012 and between February and May 2013., Results: Approximately 4% of women aged 15 to 19 and 33% of women aged 20 to 24 had Pap tests after the new guidelines were released., Conclusion: Women under the age of 25 continue to undergo unnecessary screening for cervical cancer. This excessive screening may cause physical and psychological harm and may result in unnecessary health care expenditures.

Peripheral blood smear image examination is a part of the routine work of every laboratory. The manual examination of these images is tedious, time-consuming and suffers from interobserver variation. This has motivated researchers to develop different algorithms and methods to automate peripheral blood smear image analysis. Image analysis itself consists of a sequence of steps consisting of image segmentation, features extraction and selection and pattern classification. The image segmentation step addresses the problem of extraction of the object or region of interest from the complicated peripheral blood smear image. Support vector machine (SVM) and artificial neural networks (ANNs) are two common approaches to image segmentation. Features extraction and selection aims to derive descriptive characteristics of the extracted object, which are similar within the same object class and different between different objects. This will facilitate the last step of the image analysis process: pattern classification. The goal of pattern classification is to assign a class to the selected features from a group of known classes. There are two types of classifier learning algorithms: supervised and unsupervised. Supervised learning algorithms predict the class of the object under test using training data of known classes. The training data have a predefined label for every class and the learning algorithm can utilize this data to predict the class of a test object. Unsupervised learning algorithms use unlabeled training data and divide them into groups using similarity measurements. Unsupervised learning algorithms predict the group to which a new test object belong to, based on the training data without giving an explicit class to that object. ANN, SVM, decision tree and K-nearest neighbor are possible approaches to classification algorithms. Increased discrimination may be obtained by combining several classifiers together.

Problem Addressed: The overuse of laboratory testing has increased rapidly and is contributing to the financial strain on the health care system in Canada. Moreover, a substantial proportion of ordered tests are unnecessary. In a search of all the Canadian family physician residency programs, none lists laboratory training as mandatory or as an optional elective in its curriculum., Objective of Program: To introduce family medicine residents to appropriate and efficient use of laboratory tests., Program Description: The program was run as a series of identical 4-hour small group sessions to facilitate discussion and laboratory tours. The curriculum focused on 7 key topics: problems associated with laboratory testing, sources of laboratory errors, definitions of normal and abnormal test results, appropriate use of laboratory requisition forms, laboratory quality assurance methods, laboratory collection processes, and costs of common laboratory tests. Residents were taken to a patient specimen collection site for a tour and introduction, followed by approximately 2 hours of didactic sessions, and ending with a tour of a large tertiary care testing facility., Conclusion: The program was very well received by family medicine residents and resulted in a substantial increase in residents' self-assessed knowledge of the 7 topics covered in the curriculum. It is hoped that this program will fill an important gap in residency training and support residents' competency in the "selectivity" domain of training.

Background: The purpose of this study was to assess the current usage, utilization and future direction of digital photography of gross surgical specimens in pathology laboratories across Canada., Methods: An online survey consisting of 23 multiple choice and free-text questions regarding gross digital photography was sent out to via email to laboratory staff across Canada involved in gross dissection of surgical specimens., Results: Sixty surveys were returned with representation from most of the provinces. Results showed that gross digital photography is utilized at most institutions (90.0%) and the primary users of the technology are Pathologists (88.0%), Pathologists' Assistants (54.0%) and Pathology residents (50.0%). Most respondents felt that there is a definite need for routine digital imaging of gross surgical specimens in their practice (80.0%). The top two applications for gross digital photography are for documentation of interesting/ complex cases (98.0%) and for teaching purposes (84.0%). The main limitations identified by the survey group are storage space (42.5%) and security issues (40.0%). Respondents indicated that future applications of gross digital photography mostly include teaching (96.6%), presentation at tumour boards/ clinical rounds (89.8%), medico-legal documentation (72.9%) and usage for consultation purposes (69.5%)., Conclusions: The results of this survey indicate that pathology staff across Canada currently utilizes gross digital images for regular documentation and educational reasons. They also show that the technology will be needed for future applications in teaching, consultation and medico-legal purposes.

Utilization, particularly in chemistry and molecular testing, is growing rapidly in Canada at a time when laboratory budgets are shrinking. Canadian laboratories face particular challenges as the prevailing funding model limits the scope for new revenue generation. Aggressive and coordinated interventions to reduce over-utilization will be necessary to ensure the long-term viability of the current system., (© 2013.)

Background: Strategic clinical networks, a recent development in the health system in Alberta, have been charged with bringing together front-line clinicians, researchers and policy-makers to identify variation in clinical care, and to propose standards, pathways and innovative solutions to improve access and quality of care. Here, we describe a collaborative workshop held between researchers and the Obesity, Diabetes and Nutrition Strategic Clinical Network to describe barriers to and facilitators of care for people with diabetes and to identify quality improvement interventions that should be prioritized., Methods: Through collaboration between health researchers and the strategic clinical network, and using principles of the knowledge-to-action cycle, we identified barriers to and facilitators of diabetes care using data from a patient survey and a provider focus group (5 primary care physicians and 1 diabetes educator). In addition, we identified best evidence from a systematic review of quality improvement initiatives in diabetes. This information was reviewed at a multistakeholder workshop where potential quality improvement initiatives were considered at various service levels., Results: A pilot survey involving 59 patients with diabetes and a focus group of primary care and allied health care providers identified several important barriers to optimal outcomes in diabetes care, including patient-level financial barriers to care and difficulty navigating the health system. Our collaborative discussion using the knowledge-to-action cycle prioritized feasible, evidence-based interventions to improve outcomes for patients with diabetes, including enabling care by allied health care providers and creating clear care maps and processes for system navigation., Interpretation: We identified important barriers to achieving optimal outcomes in diabetes that may be overcome through the use of evidence-based quality improvement interventions. As recommended within the knowledge-to-action cycle, future research is required to determine whether program implementation improves outcomes and is cost-effective.

Introduction: Rapid and accurate determination of platelet count is an important factor in diagnostic medicine. Traditional microscopic methods are labor intensive with variable results and are highly dependent on the individual training. Recent developments in automated peripheral blood differentials using a computerized system have shown many advantages as a viable alternative. The purpose of this paper was to determine the reliability and accuracy of the CellaVision DM 96 system with regards to platelet counts., Materials and Methods: One hundred twenty seven peripheral blood smears were analyzed for platelet count by manual microscopy, an automated hematology analyzer (Beckman Counter LH 780 or Unicel DXH 800 analyzers) and with the CellaVision DM96 system. Results were compared using the correlations and Bland-Altman plots., Results: Platelet counts from the DM96 system showed an R(2) of 0.94 when compared to manual platelet estimates and an R(2) of 0.92 when compared to the automated hematology analyzer results. Bland-Altman plots did not show any systematic bias.

Background: Leukocyte differentials are an important component of clinical care. Morphologic assessment of peripheral blood smears (PBS) may be required to accurately classify leukocytes. However, manual microscopy is labor intensive. The CellaVision DM96 is an automated system that acquires digital images of leukocytes on PBS, pre-classifies the cell type, and displays them on screen for a Technologist or Pathologist to approve or reclassify. Our study compares the results of the DM96 with manual microscopy., Methods: Three hundred and fifty-nine PBS were selected and assessed by manual microscopy with a 200 leukocyte cell count. They were then reassessed using the CellaVision DM96 with a 115 leukocyte cell count including reclassification when necessary. Correlation between the manual microscopy results and the CellaVision DM96 results was calculated for each cell type., Results: The correlation coefficients (r (2)) range from a high of 0.99 for blasts to a low of 0.72 for metamyelocytes., Conclusions: The correlation between the CellaVision DM96 and manual microscopy was as good or better than the previously published data. The accuracy of leukocyte classification depended on the cell type, and in general, there was lower correlation for rare cell types. However, the correlation is similar to previous studies on the correlation of manual microscopy with an established reference result. Therefore, the CellaVision DM96 is appropriate for clinical implementation.

Pathology informatics has evolved to varying levels around the world. The history of pathology informatics in different countries is a tale with many dimensions. At first glance, it is the familiar story of individuals solving problems that arise in their clinical practice to enhance efficiency, better manage (e.g., digitize) laboratory information, as well as exploit emerging information technologies. Under the surface, however, lie powerful resource, regulatory, and societal forces that helped shape our discipline into what it is today. In this monograph, for the first time in the history of our discipline, we collectively perform a global review of the field of pathology informatics. In doing so, we illustrate how general far-reaching trends such as the advent of computers, the Internet and digital imaging have affected pathology informatics in the world at large. Major drivers in the field included the need for pathologists to comply with national standards for health information technology and telepathology applications to meet the scarcity of pathology services and trained people in certain countries. Following trials by a multitude of investigators, not all of them successful, it is apparent that innovation alone did not assure the success of many informatics tools and solutions. Common, ongoing barriers to the widespread adoption of informatics devices include poor information technology infrastructure in undeveloped areas, the cost of technology, and regulatory issues. This review offers a deeper understanding of how pathology informatics historically developed and provides insights into what the promising future might hold.

Objective: To determine the relative effects of population size, FP and GP supply, and other specialist supply on chemistry and hematology test volumes (ie, number of tests performed)., Design: Population-level analysis using secondary data from the Calgary Health Zone for 2004 to 2009., Setting: Calgary, Alta., Main Outcome Measures: The relative effects of population size, FP and GP supply, and other specialist supply on laboratory test use., Results: Population size was the strongest predictor of test volumes in a multivariate analysis. The FP and GP supply was significantly negatively correlated with chemistry test volume (partial r(2) = 0.186, P = .045). There was a trend toward decreasing use of hematology tests with increasing FP and GP supply (partial r(2) = 0.117, P = .119)., Conclusion: The relationship between FP and GP supply and laboratory test use is complex, but increasing numbers of FPs do not necessarily indicate an increase in laboratory test use and might be associated with a decrease in test use when other factors are controlled for.

Background: Low 25-hydroxyvitamin D levels are a global health problem with northern countries such as Canada at particular risk. A number of sociodemographic factors have been reported to be associated with low vitamin D levels but prior studies have been limited by the ability of the researchers to gather this data directly from clinical trial participants. The purpose of this study was to use a novel methodology of inferring sociodemographic variables to evaluate the correlates of vitamin D levels in individuals dwelling in the City of Calgary, Alberta, Canada., Methods: We utilized data on vitamin D test results from Calgary Laboratory Services between January 1 2010 and August 31 2011. In addition to vitamin D level, we recorded age, sex, and vitamin D testing month as individual-level variables. We inferred sociodemographic variables by associating results with census dissemination areas and using Census Canada data to determine immigration status, education, median household income and first nations status as clustered variables. Associations between vitamin D status and the individual- and dissemination area-specific variables were examined using the population-averaged regression model by a generalized estimating equations approach to account for the clustering in the data., Results: 158,327 individuals were included. Age, sex, month of vitamin D testing (at an individual level), and education, immigrant status, first nations status and income (at an aggregate level) were all statistically significant predictors of vitamin D status., Conclusions: Vitamin D status was associated with a number of sociodemographic variables. Knowledge of these variables may improve targeted education and public health initiatives.

Digital pathology is a rapidly evolving niche in the world of pathology and is likely to increase in popularity as technology improves. We performed a questionnaire for pathologists and pathology residents across Canada, in order to determine their current experiences and attitudes towards digital pathology; which modalities digital pathology is best suited for; and to assess the need for training in digital pathology amongst pathology residents and staff. An online survey consisting of 24 yes/no, multiple choice and free text questions regarding digital pathology was sent out via E-mail to all members of the Canadian Association of Pathologists and pathology residents across Canada. Survey results showed that telepathology (TP) is used in approximately 43% of institutions, primarily for teaching purposes (65%), followed by operating room consults (46%). Seventy-one percent of respondents believe there is a need for TP in their practice; 85% use digital images in their practice. The top two favored applications for digital pathology are teaching and consultation services, with the main advantage being easier access to cases. The main limitations of using digital pathology are cost and image/diagnostic quality. Sixty-two percent of respondents would attend training courses in pathology informatics and 91% think informatics should be part of residency training. The results of the survey indicate that Pathologists and residents across Canada do see a need for TP and the use of digital images in their daily practice. Integration of an informatics component into resident training programs and courses for staff Pathologists would be welcomed.

Background: Although current guidelines recommend measuring lipid levels in a fasting state, recent studies suggest that nonfasting lipid profiles change minimally in response to food intake and may be superior to fasting levels in predicting adverse cardiovascular outcomes. The objective of this study was to investigate the association between fasting times and lipid levels., Methods: Cross-sectional examination of laboratory data, including fasting duration (in hours) and lipid results, was performed over a 6-month period in 2011 in a large community-based cohort. Data were obtained from Calgary Laboratory Services, Calgary, Alberta, Canada, the sole supplier of laboratory services for Calgary and surrounding areas (source population, 1.4 million persons). The main outcome measures were mean levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, and triglycerides for fasting intervals from 1 hour to more than 16 hours. After differences in individual ages were controlled for, linear regression models were used to estimate the mean levels of cholesterol subclasses at different fasting times., Results: A total of 209,180 individuals (111,048 females and 98,132 males) were included in the study. The mean levels of total cholesterol and high-density lipoprotein cholesterol differed little among individuals with various fasting times. The mean calculated low-density lipoprotein cholesterol levels showed slightly greater variations of up to 10% among groups of patients with different fasting intervals, and the mean triglyceride levels showed variations of up to 20%., Conclusion: Fasting times showed little association with lipid subclass levels in a community-based population, which suggests that fasting for routine lipid levels is largely unnecessary.

Background: Cancer is characterized by both a high mutation rate as well as high rates of cell division and cell death. We postulate that these conditions will result in the eventual mutational inactivation of genes not essential to the survival of the cancer cell, while mutations in essential genes will be eliminated by natural selection leaving molecular signatures of selection in genes required for survival and reproduction. By looking for signatures of natural selection in the genomes of cancer cells, it should therefore be possible to determine which genes have been essential for the development of a particular cancer., Methods: We provide a proof of principle test of this idea by applying a test of neutrality (Nei-Gojobori Z-test of selection) to 139 cancer-related nucleotide sequences obtained from GenBank representing 46 cancer-derived genes., Results: Among cancer associated sequences, 10 genes showed molecular evidence of selection. Of these 10 genes, four showed molecular evidence of selection in non-cancer transcripts. Among non-cancer associated sequences, eight genes showed molecular evidence of selection, with four of these also showing selection in the cancer associated sequences., Conclusions: These results provide preliminary evidence that the same genes may experience different selection pressures within normal and cancer tissues. Application of this technique could identify genes under unique selection pressure in cancer tissues and thereby indicate possible targets for therapeutic intervention.

For health scientists, knowledge translation refers to the process of facilitating uptake of knowledge into clinical practice or decision making. Since high-quality clinical research that is not applied cannot improve outcomes, knowledge translation is critical for realizing the value and potential for all types of health research. Knowledge translation is particularly relevant for areas within health care where gaps in care are known to exist, which is the case for some areas of management for people with chronic kidney disease (CKD), including assessment of proteinuria. Given that proteinuria is a key marker of cardiovascular and renal risk, forthcoming international practice guidelines will recommend including proteinuria within staging systems for CKD. While this revised staging system will facilitate identification of patients at higher risk for progression of CKD and mortality who benefit from intervention, strategies to ensure its appropriate uptake will be particularly important. This article describes key elements of effective knowledge translation strategies based on the knowledge-to-action cycle framework and describes options for effective knowledge translation interventions related to the new CKD guidelines, focusing on recommendations related to assessment for proteinuria specifically. The article also presents findings from a multidisciplinary meeting aimed at developing knowledge translation intervention strategies, with input from key stakeholders (researchers, knowledge users, decision makers and collaborators), to facilitate implementation of this guideline. These considerations are relevant for dissemination and implementation of guidelines on other topics and in other clinical settings.

Objective: To compare unsatisfactory rates between the two major liquid-based cytology (LBC) platforms, namely ThinPrep (Hologic) and SurePath (Becton Dickinson)., Design: The authors performed both a systematic review and a meta-analysis. Inclusion criteria were English language, data presented on unsatisfactory rates for either ThinPrep or SurePath, utilising actual patient samples (ie, not laboratory manipulated samples) and no manipulation using acetic acid to increase the satisfactory rate. The authors searched PubMed for articles using the keywords 'SurePath' or 'ThinPrep' and 'unsatisfactory'. References of retrieved studies were searched for additional articles. Key researchers in the field were also contacted., Participants and Interventions: Eligible studies were reviewed for rates of unsatisfactory cervical cytology smears processed on either the ThinPrep or SurePath platforms (compared with a general linear model) or data on unsatisfactory rates for both platforms for the same laboratory and the same patient population (compared with a meta-analysis using a random effects model and pooled RR)., Primary Outcome Measure: Unsatisfactory rate of cervical cytology smears., Results: A total of 1 120 418 cervical cytology smears were reported in 14 different studies using the SurePath platform for an overall unsatisfactory rate (weighted average) of 0.3%. 28 studies reported on 1 148 755 smears prepared using the ThinPrep platform for an overall unsatisfactory rate (weighted average) of 1.3%. The general linear model did not show a difference between LBC platforms when other variables were controlled for; however, the power to detect a difference (0.087) was very low. The meta-analysis performed on four studies where both ThinPrep and SurePath results were reported from the same laboratory showed fewer unsatisfactory tests from the SurePath platform (RR 0.44, 95% CI 0.25 to 0.77, p=0.004)., Conclusions: Multiple factors affect LBC unsatisfactory rates. In a meta-analysis, cervical cytology samples prepared on the SurePath platform show significantly fewer unsatisfactory smears than those prepared on the ThinPrep platform.

Background: The role that the peritumoral stroma plays in the growth of tumours is currently poorly understood. In this manuscript the morphometric characteristics of basal cell carcinoma subtypes and their associated peritumoral stromas are presented., Methods: Ninety eight digitized basal cell carcinoma histology slides were categorized as infiltrative, nodular, or superficial subtypes, and were analysed using a combination of manual and computer-assisted approaches. The morphometric characteristics of the tumour nests and their associated peritumoral stroma were quantified, and the presence of a marked immune reaction or elastosis was noted., Results: The tumour to stroma ratio was different among each tumour subtype. Elastosis was identified in a greater proportion of the infiltrative tumours., Conclusions: Quantitative differences exist between the peritumoral stroma of basal cell carcinoma subtypes. Future work exploring the relation between these morphometric differences and biochemical variations in peritumoral stroma may further our understanding of the biology of carcinoma development., Trial Registration: Not applicable.

Background: The use of digital imaging and algorithm-assisted identification of regions of interest is revolutionizing the practice of anatomic pathology. Currently automated methods for extracting the tumour regions in basal cell carcinomas are lacking. In this manuscript a colour-deconvolution based tumour extraction algorithm is presented., Findings: Haematoxylin and eosin stained basal cell carcinoma histology slides were digitized and analyzed using the open source image analysis program ImageJ. The pixels belonging to tumours were identified by the algorithm, and the performance of the algorithm was evaluated by comparing the pixels identified as malignant with a manually determined dataset.The algorithm achieved superior results with the nodular tumour subtype. Pre-processing using colour deconvolution resulted in a slight decrease in sensitivity, but a significant increase in specificity. The overall sensitivity and specificity of the algorithm was 91.0% and 86.4% respectively, resulting in a positive predictive value of 63.3% and a negative predictive value of 94.2%, Conclusions: The proposed image analysis algorithm demonstrates the feasibility of automatically extracting tumour regions from digitized basal cell carcinoma histology slides. The proposed algorithm may be adaptable to other stain combinations and tumour types.

Background: The use of adjuvant tamoxifen therapy in the treatment of estrogen receptor (ER) expressing breast carcinomas represents a major advance in personalized cancer treatment. Because there is no benefit (and indeed there is increased morbidity and mortality) associated with the use of tamoxifen therapy in ER-negative breast cancer, its use is restricted to women with ER expressing cancers. However, correctly classifying cancers as ER positive or negative has been challenging given the high reported false negative test rates for ER expression in surgical specimens. In this paper I model practice recommendations using published information from clinical trials to address the question of whether there is a false negative test rate above which it is more efficacious to forgo ER testing and instead treat all patients with tamoxifen regardless of ER test results., Methods: I USED DATA FROM RANDOMIZED CLINICAL TRIALS TO MODEL TWO DIFFERENT HYPOTHETICAL TREATMENT STRATEGIES: (1) the current strategy of treating only ER positive women with tamoxifen and (2) an alternative strategy where all women are treated with tamoxifen regardless of ER test results. The variables used in the model are literature-derived survival rates of the different combinations of ER positivity and treatment with tamoxifen, varying true ER positivity rates and varying false negative ER testing rates. The outcome variable was hypothetical 10-year survival., Results: The model predicted that there will be a range of true ER rates and false negative test rates above which it would be more efficacious to treat all women with breast cancer with tamoxifen and forgo ER testing. This situation occurred with high true positive ER rates and false negative ER test rates in the range of 20-30%., Conclusions: It is hoped that this model will provide an example of the potential importance of diagnostic error on clinical outcomes and furthermore will give an example of how the effect of that error could be modeled using real-world data from clinical trials.

Introduction: Delta checks use two specimen test results taken in succession in order to detect test result changes greater than expected physiological variation. One of the most common and serious errors detected by delta checks is specimen mix-up errors. The positive and negative predictive values of delta checks for detecting specimen mix-up errors, however, are largely unknown., Materials and Methods: We addressed this question by first constructing a stochastic dynamic model using repeat test values for five analytes from approximately 8000 inpatients in Calgary, Alberta, Canada. The analytes examined were sodium, potassium, chloride, bicarbonate, and creatinine. The model simulated specimen mix-up errors by randomly switching a set number of pairs of second test results. Sensitivities and specificities were then calculated for each analyte for six combinations of delta check equations and cut-off values from the published literature., Results: Delta check specificities obtained from this model ranged from 50% to 99%; however the sensitivities were generally below 20% with the exception of creatinine for which the best performing delta check had a sensitivity of 82.8%. Within a plausible incidence range of specimen mix-ups the positive predictive values of even the best performing delta check equation and analyte became negligible., Conclusion: This finding casts doubt on the ongoing clinical utility of delta checks in the setting of low rates of specimen mix-ups.

The extreme polymorphism of mammalian major histocompatibility (MHC) Class I and Class II alleles has been attributed to inbreeding avoidance, heterozygote advantage and pathogen driven selection for rare MHC alleles. However, MHC alleles can be classified into a limited number of allele supertypes based on the specificity of their peptide binding grooves (about 10 supertypes in the case of human MHC Class I alleles). The paradox is that if antigen presentation can be accomplished by a limited number of binding groove motifs, why are these loci so polymorphic? An unexplored driver of this complexity may be selection pressure to enhance the antigenicity and immune recognition of transplacentally acquired lymphoid allografts during pregnancy. The exchange of lymphoid cells between mother and fetus probably occurs in all pregnancies and may lead to fetal and/or maternal lymphoid microchimerism, a known cause of autoimmune disease. Natural selection may have favoured increased polymorphism at MHC Class I and Class II loci in order to improve immune surveillance of these cells and thereby reduce the incidence of maternal and fetal autoimmune disease. At the same time, selection may have favoured the retention of a limited set of allele supertypes which optimally present immunodominant antigens., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: Cervical cytology smears reported as unsatisfactory for interpretation represent an unrealized screening opportunity and may have significant laboratory and patient costs. Identifying patients at higher risk for an unsatisfactory smear could alert clinicians to take extra care in the acquisition of the smear. Few studies have examined patient characteristics that could predict an unsatisfactory cervical cytology smear. The purpose of this study was to determine the effect of patient age, day of the menstrual cycle, postmenopausal status, postpartum status, and the use of oral contraceptives on the rate of unsatisfactory cervical cytology smears., Methods: We performed a case-control study of all unsatisfactory cervical cytology smears at a large tertiary care teaching hospital over one year compared with a random sample of smears that were satisfactory for interpretation. Data were obtained from the cytology requisitions. Continuous variables were tested with unpaired t tests, and dichotomous variables were analyzed with chi-square tests. Multivariate significance was tested with binary logistic regression analysis., Results: Of all cervical cytology smears, 1.1% were reported as unsatisfactory. In univariate analyses increased age, earlier date in the menstrual cycle, and postpartum status were associated with unsatisfactory smears. However, following Bonferroni correction for multiple comparisons and multivariate regression analysis, only increased age remained a significant predictor of an unsatisfactory cervical cytology smear., Conclusion: Older women are at greater risk of having an unsatisfactory cervical cytology smear. Clinicians and public health officials must be aware of this risk and must encourage optimal collection techniques for women in this demographic group.

Increased type I error resulting from multiple statistical comparisons remains a common problem in the scientific literature. This may result in the reporting and promulgation of spurious findings. One approach to this problem is to correct groups of P-values for "family-wide significance" using a Bonferroni correction or the less conservative Bonferroni-Holm correction or to correct for the "false discovery rate" with a Benjamini-Hochberg correction. Although several solutions are available for performing this correction through commercially available software there are no widely available easy to use open source programs to perform these calculations. In this paper we present an open source program written in Python 3.2 that performs calculations for standard Bonferroni, Bonferroni-Holm and Benjamini-Hochberg corrections.

Class I human leukocyte antigen (HLA) alleles can be classified into supertypes based on the epitope specificity of their peptide binding grooves. The evolutionary origin of these supertypes has been the topic of prior research and remains an important question because of the increasing interest in HLA supertypes in the contexts of infection and cancer epidemiology and vaccine development. Here I re-examine the origins of HLA class I supertypes using the nucleotide sequences of 88 HLA-A alleles and 117 HLA-B alleles. Phylogenetic trees with ancestral character state reconstruction show that the HLA-A02, A03, and A24 supertypes largely form clades with a single ancestral origin while HLA-A01 shows multiple independent origins all from HLA-A03 ancestors. HLA-B supertypes show multiple origins for the B07, B08, and B27 supertypes, while the B44, B58, and B62 supertypes largely form clades with a single ancestor. Supertypes arising multiple times show different amino acid substitutions in each clade. These findings suggest that convergent evolution has occurred in only a few HLA allele supertypes and may indicate different evolutionary pressures shaping certain supertypes., (Copyright 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

A number of different human leukocyte antigen (HLA) allele associations with chronic myelogenous leukemia (CML) have been previously reported. The specific associations reported in one population, however, are rarely replicated in other populations. We attempted to explore these associations by performing a meta-analysis of published studies. Following a Medline search, we identified four studies which presented raw data on all allele associations with CML (significant and non-significant). Meta-analysis of these revealed a significant risk association with the HLA-A*02 (pooled odds ratio 1.33, 95% confidence interval 1.10-1.61) allele and a significant protective effect with the HLA-B*35 allele (pooled odds ratio 0.64, 95% confidence interval 0.48-0.86). To our knowledge this is the first study to demonstrate the epidemiologic association between HLA-A*02 and the risk of CML, and we discuss this in the context of recent immunological studies reporting data on BCR-ABL fusion peptide presentation and subsequent immune response. Our findings suggest that individual epidemiological studies may lack statistical power, or may have other interfering factors which prevent the unmasking of overall associations. Meta-analyses of published studies may overcome these limitations and may prove useful in uncovering allele-disease associations.

The adaptive immune system, fine tuned through millions of years of vertebrate evolution, discriminates self from foreign antigens through the deletion of auto-reactive clones and/or tolerization to self antigens. In this system, commonly encountered antigens should be recognized as self while rarely encountered antigens such as microbial or cancer derived molecules should be recognized as foreign. Throughout evolutionary history, the availability of cryptic self-antigens for presentation was enhanced though immune processing of damaged tissues due to infections, parasites and trauma - in other words, the hardscrabble conditions that prevailed throughout the vast majority of our evolutionary past. In situations where chronic tissue injury is reduced there is an increase in the incidence of autoimmune disease. A unifying hypothesis is thereby provided to explain the major epidemiological trends in autoimmune diseases, namely, (1) an historic increase in incidence, (2) increase in the incidence with increasing latitude, (3) increase in the incidence with higher socioeconomic status.

Chronic myelogenous leukemia (CML) results from a translocation (9;22), which creates an immunogenically active BCR-ABL fusion protein. Previous authors have reported both positive and negative human leukocyte antigen (HLA) associations with CML, possibly as the result of different antigenic peptide presentation capabilities. We examined HLA Class I and Class II antigen polymorphisms in 31 patients with CML and compared these with 258 control individuals drawn from Maritime Canada. HLA-B*13 (odds ratios (OR) 4.92, 95% confidence intervals (CI) 1.70-14.24), HLA-B*55 (OR 4.50, 95%CI 1.07-18.99), and HLA-DRB1*16 (OR 4.07, 95%CI 1.17-14.09) were all statistically significant risk markers for CML. After a Bonferroni correction for Type I error was applied, only HLA-B*13 remained statistically significant as a risk marker for CML. No HLA antigens were found to be protective. The lack of reproducibility of HLA antigen associations with CML suggests that these associations are population-specific and may not be due to HLA antigen-restricted differences in CML antigen presentation.

Metastases to the pineal gland are rare and reported cases have consisted primarily of gastrointestinal and lung primary malignancies. Here we present the case of a 66-year-old female with autosomal dominant polycystic kidney and liver disease who was found at autopsy to have an unrecognized infiltrating ductal adenocarcinoma of the pancreas with metastases to the liver, lungs and pineal gland. As far as we are aware, this is the first report of a metastasis of infiltrating ductal adenocarcinoma of the pancreas to the pineal gland.