Serum 25-hydroxyvitamin D and risk of cancer in a large community population under investigation for cardiovascular disease: a retrospective cohort study.

OBJECTIVES: It remains unclear whether vitamin D status is related to cancer risk. We examined this relationship using laboratory, administrative and survey data. DESIGN: Retrospective cohort study. SETTING: All care settings within Calgary, Alberta, Canada and surrounding rural communities. PARTICIPANTS: Patients tested for serum 25-hydroxyvitamin D from 2009 to 2013 without a past cancer diagnosis but with an ECG and body mass index ±3 months from testing were included. Age, sex, mean hours of daylight during month of testing were linked to census dissemination area-level indicators of socioeconomic status measured in 2011. PRIMARY AND SECONDARY OUTCOME MEASURES: Hospital discharge diagnoses for any cancer, major cancer (colorectal, breast, lung, prostate, skin) and other cancers >3 months from testing from 2009 to 2016. Cox proportional hazard models were used to examine associations with incident cancer after adjusting for potential confounders. Interactions were tested using multiplicative terms. RESULTS: Among 72 171 patients, there were 3439 cancer diagnoses over a median of 5.9 years. After adjustment, increasing quartile of serum 25-OH vitamin D was significantly associated with an increased risk of any cancer and major cancer, however this was completely driven by an increased risk of skin cancer (Q4 vs Q1: HR=2.56, 95% CI 1.70 to 3.86, p for linear trend <0.01). This association was strengthened among individuals residing in communities with higher proportions of non-citizens, recent immigrants, visible (non-white) minorities and those not speaking an official Canadian language (English or French) at home. CONCLUSIONS: Higher vitamin D status was associated with a greater risk of skin cancer in a large community population under investigation for cardiovascular disease. This association was likely due to sun exposure and may be modified by community variation in vitamin D supplementation.

Serum 25-hydroxyvitamin D, cardiovascular risk markers, and incident cardiovascular disease in a high risk community population.

BACKGROUND: It is unclear whether vitamin D status is related to cardiovascular risk beyond that explained by conventional risk markers. We examined the relationship between serum 25-hydroxy (OH) vitamin D and incident cardiovascular disease (CVD; heart attack/stroke) after adjusting for individual- and community-level covariates from laboratory, administrative and survey data. METHODS: Patients receiving their first 25-OH vitamin D test in Calgary, Alberta from 2009 to 2013 without a past CVD diagnosis but an electrocardiogram and body mass index (BMI) +/- 3 months from testing were included. The following was merged to this data: first results for laboratory-measured CVD risk markers (lipid profile, fasting plasma glucose, and HbA1c) measured +/- 3 months from testing; Census Dissemination Area (CDA)-level indicators of socioeconomic status (SES) in 2011; and CVD diagnoses > 3 months from testing between 2009 and 2016. Linear and Poisson regression were used to examine associations between 25-OH vitamin D quartile and covariates, and Cox proportional hazard models were used to examine associations with incident CVD before and after adjusting for covariates. RESULTS: Among 72 348 patients, there were 1898 CVD events over a median of 6.0 years. Increasing quartile of 25-OH vitamin D was associated with improved lipid and glycemic profiles (p < 0.01), higher proportion of CDA-level indicators of high SES (p < 0.01), and a lower risk of CVD (Q4 vs Q1: HR: 0.72, 95% CI: 0.63-0.81, p for trend < 0.01) after adjusting for age, sex and average daily hours of sunlight during month of testing. The association with CVD was unchanged after adjusting for BMI, slightly attenuated after adjusting for SES but completely abolished after adjusting for laboratory-measured cardiovascular risk markers. CONCLUSIONS: Vitamin D status likely offers no additional information on CVD risk over conventional laboratory-measured risk markers.

Simple Laboratory Test-Based Risk Scores in Coronary Catheterization: Development, Validation, and Comparison to Conventional Risk Factors.

BACKGROUND: We developed and validated laboratory test-based risk scores (i.e., lab risk scores) to reclassify mortality risk among patients undergoing their first coronary catheterization. METHODS: Patients were catheterized between 2009 and 2015 in Calgary, Alberta, Canada (n = 14 135, derivation cohort), and in Edmonton, Alberta, Canada (n = 12 143, validation cohort). Logistic regression with group LASSO (least absolute shrinkage and selection operator) penalty was used to select quintiles of the last laboratory tests (red blood cell count, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular volume, red cell distribution width, platelet count, total white blood cell count, plasma sodium, potassium, chloride, CO2, international normalized ratio, estimated glomerular filtration rate) performed <30 days before catheterization and by age and sex that were significantly associated with death ≤60 and >60 days after catheterization. Follow-up was until 2016. Risk scores were developed from significant tests, internally validated in Calgary among bootstrap samples and externally validated in Edmonton after recalibration using coefficients developed in Calgary. Interaction tests were performed, and net reclassification improvement vs conventional demographic and clinical risk factors was determined. RESULTS: Lab risk scores were strongly associated with mortality (29-40× for top vs bottom quintile, P for trends <0.01), had good discrimination and were well calibrated in Calgary (C = 0.80-0.85, slope = 0.99-1.01) and Edmonton (C = 0.80-0.82; slope = 1.02-1.05)-similar to demographic and clinical risk factors alone. Associations were attenuated by several comorbidities; however, scores appropriately reclassified 11%-20% of deaths (both follow-up periods) and 6%-9% of survivors (>60 days) after catheterization vs demographic and clinical risk factors. CONCLUSIONS: In 2 populations of patients undergoing their first coronary catheterization, risk scores based on simple laboratory tests were as powerful as a combination of demographic and clinical risk factors in predicting mortality. Lab risk scores should be used for patients undergoing coronary catheterization.

Intervention to Reduce Unnecessary Glucose Tolerance Testing in Pregnant Women.

BACKGROUND: Gestational diabetes mellitus (GDM) can be diagnosed in pregnant women by increased fasting plasma glucose alone, which eliminates the need for performing a 75 g oral glucose tolerance test (OGTT). If whole blood glucose meters are used to triage fasting samples in order to decide whether to give the glucose drink, a cutpoint with appropriate sensitivity and specificity for elevated fasting plasma glucose is needed. METHODS: The number of GDM diagnoses by increased fasting plasma glucose alone was determined from specimens collected and tested at core laboratories in urban hospitals, rural health centers, and from specimens collected at patient phlebotomy service centers (PSCs) for plasma testing at a central laboratory. The number of glucose drinks avoided was counted after implementing the diagnostic cutoff of ≥95 mg/dL (5.3 mmol/L) at urban hospitals and rural health centers, which have on-site plasma testing, and after selecting a PSC meter fasting venous whole blood glucose cutpoint after calculating sensitivity and specificity for plasma glucose ≥95 mg/dL (5.3 mmol/L) using logistic regression. RESULTS: Among 4850 OGTTs, there were 1315 GDM diagnoses annually, of which 409 were from increased fasting plasma glucose. Ninety-one percent of OGTTs were performed at PSCs. If a fasting plasma glucose cutpoint of ≥95 mg/dL (5.3 mmol/L) was implemented at urban hospitals and rural health centers and a meter fasting venous whole blood glucose cutpoint of ≥108 mg/dL (6.0 mmol/L) (25% sensitivity, 99.9% specificity) was implemented at PSCs, the drink would be appropriately avoided by 145 patients/year, and inappropriately avoided by 3 patients/year. After implementing these cutpoints, the drink was appropriately avoided in 91 patients during a 36-week period, with none inappropriately avoiding it. CONCLUSION: Modifying fasting glucose cutpoints reduced unnecessary diagnostic OGTTs in pregnant women.

Elimination of 72-Hour Quantitative Fecal Fat Testing by Restriction, Laboratory Consultation, and Evaluation of Specimen Weight and Fat Globules.

BACKGROUND: The 72-h quantitative fecal fat test has been mostly obsolete for many years. Our objective was to reduce and eliminate the use of this test, while providing suitable alternatives. METHODS: We assessed (2010-2016) utilization of the fecal fat test in Calgary, Central Alberta, and Southern Alberta, Canada. Alternatives were identified through literature review and consultation with gastroenterologist stakeholders. Logistic regression and ROC curves were used to characterize discrimination power of 72-h specimen weight on abnormal fat excretion. This was also examined in 91 subspecimens that were additionally tested for the presence of fat globules. RESULTS: As 69% of fecal fat tests (total, 106/year) were on adults (age ≥ 18), stakeholders agreed that adult specimens should not be tested until ordering physicians consulted with a clinical biochemist. This change reduced fecal fat testing by 81% to 20/year in 2015. The 72-h specimen weight was a significant predictor of abnormal fat excretion [P < 0.001; area under curve (AUC) = 0.75-0.79, n = 115-417] in historic fecal fat data. A similar result was observed among subspecimens (AUC = 0.70), which improved when additionally considering the presence of fat globules (AUC = 0.74). Stakeholders consented to replacing fecal fat with a comparison of specimen weight to cutpoints with 80% specificity for abnormal fat excretion, and the test for fat globules. CONCLUSION: Through stakeholder engagement, we implemented changes that eliminated 72-h quantitative fecal fat testing in a large geographic region in Alberta, Canada. Future fecal fat orders would be reflexed to an assessment of 72-h specimen weight and a qualitative test for fat globules in stool.

Mean Abnormal Result Rate: Proof of Concept of a New Metric for Benchmarking Selectivity in Laboratory Test Ordering.

OBJECTIVES: There is a need to develop and validate new metrics to access the appropriateness of laboratory test requests. METHODS: The mean abnormal result rate (MARR) is a proposed measure of ordering selectivity, the premise being that higher mean abnormal rates represent more selective test ordering. As a validation of this metric, we compared the abnormal rate of lab tests with the number of tests ordered on the same requisition. We hypothesized that requisitions with larger numbers of requested tests represent less selective test ordering and therefore would have a lower overall abnormal rate. RESULTS: We examined 3,864,083 tests ordered on 451,895 requisitions and found that the MARR decreased from about 25% if one test was ordered to about 7% if nine or more tests were ordered, consistent with less selectivity when more tests were ordered. We then examined the MARR for community-based testing for 1,340 family physicians and found both a wide variation in MARR as well as an inverse relationship between the total tests ordered per year per physician and the physician-specific MARR. CONCLUSIONS: The proposed metric represents a new utilization metric for benchmarking relative selectivity of test orders among physicians.

Generating unique IDs from patient identification data using security models.

BACKGROUND: The use of electronic health records (EHRs) has continued to increase within healthcare systems in the developed and developing nations. EHRs allow for increased patient safety, grant patients easier access to their medical records, and offer a wealth of data to researchers. However, various bioethical, financial, logistical, and information security considerations must be addressed while transitioning to an EHR system. The need to encrypt private patient information for data sharing is one of the foremost challenges faced by health information technology. METHOD: We describe the usage of the message digest-5 (MD5) and secure hashing algorithm (SHA) as methods for encrypting electronic medical data. In particular, we present an application of the MD5 and SHA-1 algorithms in encrypting a composite message from private patient information. RESULTS: The results show that the composite message can be used to create a unique one-way encrypted ID per patient record that can be used for data sharing. CONCLUSION: The described software tool can be used to share patient EMRs between practitioners without revealing patients identifiable data.

Prostate-specific antigen velocity is not better than total prostate-specific antigen in predicting prostate biopsy diagnosis.

OBJECTIVES: 1.) Identify whether prostate-specific antigen velocity improves the ability to predict prostate biopsy diagnosis. 2.) Test whether there is an increase in the predictive capability of models when Gleason 7 prostate cancers are separated into a 3+4 and a 4+3 group. DESIGN AND METHODS: Calgary Laboratory Services' Clinical Laboratory Information System was searched for prostate biopsies reported between January 1, 2009 and December 31, 2013. Total prostate-specific antigen tests were recorded for each patient from January 1, 2007 to the most recent test before their recorded prostate biopsy. The data set was divided into the following three groups for comparison; benign, all prostate cancer and Gleason 7-10. The Gleason grade 7-10 group was further divided into 4+3 and 3+4 Gleason 7 prostate cancers. Prostate-specific antigen velocity was calculated using four different methods found in the literature. Receiver operator curves were used to assess operational characteristics of the tests. RESULTS: 4622 men between the ages of 40-89 with a prostate biopsy were included for analysis. Combining prostate-specific antigen velocity with total prostate-specific antigen (AUC=0.570-0.712) resulted in small non-statistically significant changes to the area under the curve compared to the area under the curve of total prostate-specific antigen alone (AUC=0.572-0.699). There were marked increases in the area under curves when 3+4 and 4+3 Gleason 7 cancers were separated. CONCLUSIONS: Prostate-specific antigen velocity does not add predictive value for prostate biopsy diagnosis. The clinical significance of the prostate specific antigen test can be improved by separating Gleason 7 prostate cancers into a 3+4 and 4+3 group.

A population study of fasting time and serum prostate-specific antigen (PSA) level.

Prostate cancer is one of the most common cancers in men. Traditional screening and diagnostic methods include digital rectal examinations (DREs), biopsies and serum prostate-specific antigen (PSA) tests, with the latter being the more popular. PSA is a biomarker for prostate cancer; however, it is highly sensitive to external factors as well as other prostate diseases. As such, the reliability of of the serum PSA level as a sole screening and diagnostic tool for prostate cancer is controversial. Recently, it has been shown that fasting extremes can affect concentrations of serum chemistry analytes, thus raising the question of whether or not fasting has an effect on the highly sensitive PSA biomarker. Patients testing for serum PSA levels are often concomitantly submitting to other tests that require fasting, subjecting certain patients to a fasting PSA level while others not. The objective of this study was to investigate whether this discrepancy in fasting state translates into an effect on serum PSA levels. Serum PSA levels and fasting time records for 157 276 men who underwent testing at Calgary Laboratory Services (CLS; Calgary, Alberta, Canada) between 01 January 2010 and 31 March 2013 were accessed. Linear regression models of mean PSA levels and fasting times revealed a statistically important relationship at certain fasting times. Applying a dynamic mathematical model to explore the clinical effect of fasting suggests minimal impact on serum PSA result interpretation. Thus, patients can be tested for serum PSA levels regardless of their fasting state.

Population genetics of cancer cell clones: possible implications of cancer stem cells.

BACKGROUND: The population dynamics of the various clones of cancer cells existing within a tumour is complex and still poorly understood. Cancer cell clones can be conceptualized as sympatric asexual species, and as such, the application of theoretical population genetics as it pertains to asexual species may provide additional insights. RESULTS: The number of generations of tumour cells within a cancer has been estimated at a minimum of 40, but high cancer cell mortality rates suggest that the number of cell generations may actually be in the hundreds. Such a large number of generations would easily allow natural selection to drive clonal evolution assuming that selective advantages of individual clones are within the range reported for free-living animal species. Tumour cell clonal evolution could also be driven by variation in the intrinsic rates of increase of different clones or by genetic drift. In every scenario examined, the presence of cancer stem cells would require lower selection pressure or less variation in intrinsic rates of increase. CONCLUSIONS: The presence of cancer stem cells may result in more rapid clonal evolution. Specific predictions from theoretical population genetics may lead to a greater understanding of this process.

Impact of a reporting template on thyroid fine needle aspiration cytology reporting and cytohistologic concordance.

BACKGROUND: Reporting templates are increasingly common in all fields of pathology. In this paper, we present an assessment of the impact of a thyroid fine needle aspiration cytology (FNAC) template on diagnostic classification and cytohistologic concordance. MATERIALS AND METHODS: A thyroid FNAC reporting template was developed and introduced at a university teaching hospital. We examined FNAC reports for a five-month period before introduction of the template and compared these to the five month period after the template introduction. We recorded diagnostic categorization as well as cytohistologic correlation. RESULTS: A total of 168 cases were identified in the five month period prior to the introduction of the reporting template and 172 cases in the five month period after the introduction of the reporting template. The template appeared to improve the diagnostic precision of benign conditions without altering the proportion of cases classified as unsatisfactory, benign or abnormal. There was no significant difference in the rate of cytohistologic concordance before and after the template introduction. CONCLUSIONS: The introduction of a reporting template for thyroid FNAC improved diagnostic precision of benign conditions and did not alter the general diagnostic classification or cytohistologic concordance.

Evolutionary medicine: update on the relevance to family practice.

OBJECTIVE: To review the relevance of evolutionary medicine to family practice and family physician training. QUALITY OF EVIDENCE: Articles were located through a MEDLINE search, using the key words evolution, Darwin, and adaptation. Most references presented level III evidence (expert opinion), while a minority provided level II evidence (epidemiologic studies). MAIN MESSAGE: Evolutionary medicine deals with the interplay of biology and the environment in the understanding of human disease. Yet medical schools have virtually ignored the need for family physicians to have more than a cursory knowledge of this topic. A review of the main trends in this field most relevant to family practice revealed that a basic knowledge of evolutionary medicine might help in explaining the causation of diseases to patients. Evolutionary medicine has also proven key to explaining the reasons for the development of antibiotic resistance and has the potential to explain cancer pathogenesis. As an organizing principle, this field also has potential in the teaching of family medicine. CONCLUSION: Evolutionary medicine should be studied further and incorporated into medical training and practice. Its practical utility will be proven through the generation of testable hypotheses and their application in relation to disease causation and possible prevention.