The impact of inter-laboratory glucose bias on the diagnosis of gestational diabetes mellitus: Comparison of common automated central laboratory methods.

BACKGROUND AND AIMS: The diagnosis of gestational diabetes mellitus (GDM) is based exclusively on glucose measurements, which are highly influenced by pre-analytical and analytical factors. Therefore, poor agreement across laboratories may affect the prevalence of GDM. We aimed to determine the inter-laboratory bias of glucose measurements and the impact on GDM prevalence. MATERIAL AND METHODS: A prospective cohort study of women (n = 110) referred for second-trimester GDM diagnostics using a 75 g oral glucose tolerance test. Maternal glucose was assessed from venous plasma at fasting, 1 h and 2 h. Venous blood were collected in Fluoride Citrate tubes and frozen. Samples were analyzed at five central laboratories using four different automated glucose Hexokinase methods and GDM prevalence was evaluated according to WHO2013 diagnostic criteria. RESULTS: Maximum inter-laboratory bias was 0.19, 0.30 and 0.27 mmol/L in fasting, 1 h and 2 h samples, respectively. GDM prevalence ranged 30.0-41.1% across laboratories. CONCLUSION: Inter-laboratory bias for mean venous glucose was low and within desirable limits. Nonetheless, the impact on GDM prevalence was considerable, which may inappropriately affect clinical practice.

Elevated Hemolysis Index is associated with higher risk of cardiovascular diseases.

OBJECTIVES: In vivo hemolysis is associated with thromboembolism. Although an increased Hemolysis Index (HI) can be due to in vitro as well as in vivo hemolysis, both reflects a more fragile erythrocyte population. We therefore hypothesized that HI above upper reference limit would be associated with an increased risk of cardiovascular disease (CVD). METHODS: We identified persons with two elevated HI (HI+) from blood samples analyzed at a university hospital laboratory from 2012 to 2017. We compared their risk of CVD with the risk in matched comparators with normal HI and from the general population. HI+ persons and comparators were followed from start date (date of the second elevated HI) until the first of the main outcome: CVD, emigration, death, or end of observation time on December 31, 2018. RESULTS: In 43,102 unique HI+ persons, the risk of developing CVD was 40% higher compared with the general population and 13% higher compared with the matched blood sample cohort. HI+ was associated with a significantly increased cumulative incidence of both arterial and venous CVD compared with the matched blood sample cohort and the general population (respectively 47 and 14% for arterial CVD; 78 and 24% for venous CVD). Moreover, overall mortality risk was significantly higher in patients with HI+ than in the two comparator groups. CONCLUSIONS: Elevated HI is associated with increased risk of arterial and venous CVD and with increased mortality. Our findings imply that HI may contribute as a CVD risk biomarker.

Deep learning detects and visualizes bleeding events in electronic health records.

BACKGROUND: Bleeding is associated with a significantly increased morbidity and mortality. Bleeding events are often described in the unstructured text of electronic health records, which makes them difficult to identify by manual inspection. OBJECTIVES: To develop a deep learning model that detects and visualizes bleeding events in electronic health records. PATIENTS/METHODS: Three hundred electronic health records with International Classification of Diseases, Tenth Revision diagnosis codes for bleeding or leukemia were extracted. Each sentence in the electronic health record was annotated as positive or negative for bleeding. The annotated sentences were used to develop a deep learning model that detects bleeding at sentence and note level. RESULTS: On a balanced test set of 1178   sentences, the best-performing deep learning model achieved a sensitivity of 0.90, specificity of 0.90, and negative predictive value of 0.90. On a test set consisting of 700 notes, of which 49 were positive for bleeding, the model achieved a note-level sensitivity of 1.00, specificity of 0.52, and negative predictive value of 1.00. By using a sentence-level model on a note level, the model can explain its predictions by visualizing the exact sentence in a note that contains information regarding bleeding. Moreover, we found that the model performed consistently well across different types of bleedings. CONCLUSIONS: A deep learning model can be used to detect and visualize bleeding events in the free text of electronic health records. The deep learning model can thus facilitate systematic assessment of bleeding risk, and thereby optimize patient care and safety.

Verification of the hemolysis index measurement: imprecision, accuracy, measuring range, reference interval and impact of implementing analytically and clinically derived sample rejection criteria.

Automated spectrophotometric measurement of hemolysis index (HI) allows rapid and cost-effective assessment of hemolysis interference. We evaluated the analytical performance of HI on two different platforms. Further, the impact of implementing analytically and clinically derived sample rejection criteria was investigated. Precision profiles were established, and analytical error was assessed by comparison with the reference method for hemoglobin measurement on Architect c8000/c16000 (Abbott) and Cobas c702 (Roche Diagnostics) instruments. The impact of a more analyte-specific cut off based on analytical and biologival variation was examined for five hemolysis-sensitive plasma analyses according to European recommendations. Lastly, a reference interval was established for the HI on Cobas, using the CLSI C28A3c nonparametric method. Imprecision for HI of 0.6-3.0 % for Architect and 1.5-4.5 % for Cobas was considered acceptable, which also applied for trueness in the measuring tange > 2 g/L. If cutoffs based on analytical and biological variation were used to manage results from hemolyzed samples, more potassium, LDH, conjugated bilirubin and phosphate results would be suppressed. Considering RCV only LDS remained sensitive to hemolysis. The Cobas-based HI reference interval was established to 0.01-0.16 g/L. Thorough verification of the HI on two different clinical chemistry analyzers reveals acceptable analytical performance. HI cutoffs suggested by manufacturers may be optimized by clinical laboratories using analytical and/or biological variation. A reference interval for the HI analysis is relevant as the analysis has been suggested as a diagnostic tool in the assessment of in vivo hemolysis.

Laboratory Tests and Outcome for Patients with Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 causes coronavirus disease 2019 (COVID-19) and poses substantial challenges for healthcare systems. With a vastly expanding number of publications on COVID-19, clinicians need evidence synthesis to produce guidance for handling patients with COVID-19. In this systematic review and meta-analysis, we examine which routine laboratory tests are associated with severe COVID-19 disease. CONTENT: PubMed (Medline), Scopus, and Web of Science were searched until March 22, 2020, for studies on COVID-19. Eligible studies were original articles reporting on laboratory tests and outcome of patients with COVID-19. Data were synthesized, and we conducted random-effects meta-analysis, and determined mean difference (MD) and standard mean difference at the biomarker level for disease severity. Risk of bias and applicability concerns were evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. SUMMARY: 45 studies were included, of which 21 publications were used for the meta-analysis. Studies were heterogeneous but had low risk of bias and applicability concern in terms of patient selection and reference standard. Severe disease was associated with higher white blood cell count (MD, 1.28 ×109/L), neutrophil count (MD, 1.49 ×109/L), C-reactive protein (MD, 49.2 mg/L), lactate dehydrogenase (MD, 196 U/L), D-dimer (standardized MD, 0.58), and aspartate aminotransferase (MD, 8.5 U/L); all p < 0.001. Furthermore, low lymphocyte count (MD -0.32 × 109/L), platelet count (MD -22.4 × 109/L), and hemoglobin (MD, -4.1 g/L); all p < 0.001 were also associated with severe disease. In conclusion, several routine laboratory tests are associated with disease severity in COVID-19.

Quality Control of Preanalytical Handling of Blood Samples for Future Research: A National Survey.

BACKGROUND: Assessment and control of preanalytical handling of blood samples for future research are essential to preserve integrity and assure quality of the specimens. However, investigation is limited on how quality control of preanalytical handling of blood samples is performed by biobanks. METHODS: A questionnaire was sent to all Danish departments of clinical biochemistry, all Danish departments of clinical immunology, the Danish Health Surveillance Institution and the Danish Cancer Society. The questionnaire consisted of questions regarding preanalytical handling of samples for future research. The survey was carried out from October 2018 until the end of January 2019. RESULTS: A total of 22 departments (78%) replied, of which 17 (77%) performed preanalytical quality control of the blood samples. This quality control consisted of patient preparation, temperature surveillance of freezers, maintenance of centrifuges, and visual inspection for hemolysis, lipemia, and sample volume. Automated sample check for hemolysis, icterus, and lipemia interferences was performed by 41% of respondents, not performed by 50% of respondents, and 9% did not answer. The majority (55%) of the participants stated that they had no local standard operating procedure for preanalytical handling of samples for research projects. CONCLUSIONS: The preanalytical phase for blood samples obtained and preserved for future research in Denmark is highly heterogeneous, although many aspects (e.g., hemolysis, which also affects DNA analyses, metabolomics, and proteomics) seems highly relevant to document. Our findings emphasize the need to optimize and standardize best practices for the preanalytical phase for blood samples intended for use in future research projects.

Use of clinical data and acceleration profiles to validate pneumatic transportation systems.

Background Modern pneumatic transportation systems (PTSs) are widely used in hospitals for rapid blood sample transportation. The use of PTS may affect sample integrity. Impact on sample integrity in relation to hemolysis and platelet assays was investigated and also, we wish to outline a process-based and outcome-based validation model for this preanalytical component. Methods The effect of PTS was evaluated by drawing duplicate blood samples from healthy volunteers, one sent by PTS and the other transported manually to the core laboratory. Markers of hemolysis (potassium, lactate dehydrogenase [LD] and hemolysis index [HI]) and platelet function and activation were assessed. Historic laboratory test results of hemolysis markers measured before and after implementation of PTS were compared. Furthermore, acceleration profiles during PTS and manual transportation were obtained from a mini g logger in a sample tube. Results Hand-carried samples experienced a maximum peak acceleration of 5 g, while peaks at almost 15 g were observed for PTS. No differences were detected in results of potassium, LD, platelet function and activation between PTS and manual transport. Using past laboratory data, differences in potassium and LD significantly differed before and after PTS installation for all three lines evaluated. However, these estimated differences were not clinically significant. Conclusions In this study, we found no evidence of PTS-induced hemolysis or impact on platelet function or activation assays. Further, we did not find any clinically significant changes indicating an acceleration-dependent impact on blood sample quality. Quality assurance of PTS can be performed by surveilling outcome markers such as HI, potassium and LD.

Falsely prolonged activated partial thromboplastin time - a pre- and post-analytical issue.

This case highlights two common pre-analytical problems identified in routine coagulation testing of activated partial thromboplastin time (aPTT), which were overlooked because of a concurrent flag code indicating no coagulation and the result was replaced by asterisks. It concerns a boy with gastrointestinal bleeding and prolonged aPTT > 300 seconds, which raised the suspicion of haemophilia. When all other coagulation parameters (including specific coagulation factors VIII and IX) turned out to be normal, aPTT was re-measured using another analysis principle, which revealed a normal aPTT. The primary aPTT result turned out to be aborted due to concurrent haemolysis and lipaemia, but was erroneously interpreted as prolonged coagulation. The lesson is awareness of the possibility of numerous flag codes on the same sample overruling each other, and awareness on the responsibility in the post-analytical phase that must be carried by increased educational focus and by the manufacturers.

Proteomic Discovery and Validation of the Confounding Effect of Heparin Administration on the Analysis of Candidate Cardiovascular Biomarkers.

BACKGROUND: Several plasma proteins have been suggested as markers for a variety of cardiovascular conditions but fail to qualify in independent patient cohorts. This may relate to interference of medication on plasma protein concentrations. We used proteomics to identify plasma proteins that changed in concentration with heparin administration and therefore potentially may confound their evaluation as biomarkers in situations in which heparin is used. METHODS: We used a proteomic approach based on isobaric tagging and nano-LC-MS/MS analysis to quantify several hundred proteins in a discovery study in which individual plasma samples from 9 patients at intravascular ultrasound follow-up 12 months after an acute myocardial infarction before heparin administration and 2, 15, and 60 min after heparin administration; we validated our findings in 500 individual plasma samples obtained at admission from patients with suspected ST segment elevation myocardial infarction (STEMI), of whom 363 were treated with heparin before admission. RESULTS: In the discovery study, 25 of 653 identified plasma proteins displayed a changed concentration after heparin administration (Bonferroni-corrected P value at P < 7.66 × 10-5). Fourteen of the proteins changed significantly among heparin-treated patients in the validation study (nominal significance level of P < 6.92 × 10-5). Among heparin-affected proteins in both the discovery study and the validation study were midkine, spondin 1, secreted frizzled-like protein 1, lipoprotein lipase, and follistatin, all previously associated with STEMI. CONCLUSIONS: Medications such as heparin administration given before blood sampling may confound biomarker discovery and should be carefully considered in such studies.

Sample Type and Storage Conditions Affect Calprotectin Measurements in Blood.

BACKGROUND: Calprotectin, a complex of calcium-binding proteins, is abundant in granulocytes. Increased levels of plasma calprotectin have been found in patients with inflammatory and autoimmune diseases. However, a number of preanalytical factors may affect calprotectin measurement in blood samples. METHODS: Twelve blood samples [4 tubes, 1 each of lithium-heparin (Li-heparin), EDTA, and serum] were drawn from each of 14 healthy individuals. To evaluate the effect of temperature and storage time in the lag time between collection and centrifugation, samples were kept for 2 h at 4 °C, 20 °C, or 37 °C, before centrifugation. Leukocyte, neutrophil, and monocyte counts were measured in EDTA samples on a Sysmex XN-10 hematology analyzer to investigate the relationship between calprotectin concentrations and the granulocyte count. RESULTS: Calprotectin measurements in EDTA samples were not influenced by temperature or time lag between collection and analysis. Compared to EDTA plasma, significantly higher calprotectin concentrations were found in serum and Li-heparin plasma samples. Furthermore, calprotectin concentrations increased in serum and Li-heparin samples when stored at higher temperatures. There was a linear relationship between the serum calprotectin concentration and neutrophil count in EDTA whole blood. CONCLUSIONS: EDTA is the most suitable anticoagulant for determination of calprotectin in plasma, as this sample matrix does not seem to be affected by temperature or time between sample collection and analysis. Of particular note, neutrophil activation by either clotting or centrifugation should be avoided during the preanalytical process.

Perception of drug teratogenicity among general practitioners and specialists in obstetrics/gynecology: a regional and national questionnaire-based survey.

BACKGROUND: Estimating the true risk of fetal malformations attributable to the use of medications is difficult and perception of risk by health professionals will impact their counseling and treatment of patients who need medication during pregnancy. The objective of this study was to assess the perception of the teratogenic risk of 9 commonly and 3 rarely prescribed drugs among general practitioners and specialists in obstetrics/gynecology. METHODS: All 811 general practitioners in the Region of Southern Denmark and all 502 specialist obstetricians/gynecologists in Denmark as a whole were invited to participate in the study based on an online questionnaire. Medians and interpercentile ranges of the perceived background risk and perceived risks for each of the drugs were included in the questionnaire. RESULTS: One hundred forty three (18 %) general practitioners and 138 (27 %) obstetricians/gynecologists participated. Estimates provided by the participants were generally in accordance with current knowledge of drugs with established safety during pregnancy. Perceptions of risks associated with warfarin and retinoid exposure were severely underestimated. CONCLUSIONS: Understanding of teratogenic background risk and specific risks associated with in utero exposure to 12 different drugs generally approached the established knowledge. The risk associated with warfarin and retinoid exposure was severely underestimated by both groups of health care professionals, while general practitioners specifically overestimated the risk of sertraline and citalopram to some extent. In Denmark, general practitioners can prescribe antidepressants, and even minor misconceptions of the teratogenic potential of citalopram and sertraline may be of clinical relevance. In Denmark, systemic retinoids can only be prescribed by a dermatologist, and warfarin treatment is only rarely initiated in women of the fertile age without involvement of specialists in internal medicine. Hence, the active knowledge on the teratogenic potential of these drugs is likely to be less accurate among general practitioners and obstetricians/gynecologists; although still of clinical importance since these specialists are largely involved in the counselling of pregnant women.

Thrombophilia prevalence among women with placenta-mediated pregnancy complications.

OBJECTIVE: To evaluate the prevalence of thrombophilia in patients with placenta-mediated pregnancy complications (PMPC). METHODS: Patients referred for thrombophilia testing at Odense University Hospital, Denmark, owing to PMPC between January 1, 2010 and December 31, 2014, were included in the present retrospective study. Data collected from patient medical records included the type of PMPC, history of previous thrombosis, and arterial thrombosis risk factors. RESULTS: A total of 103 patients were included in the study; 25 (24.3%) were diagnosed with thrombophilia. Among the study population, factor V Leiden was the most dominant thrombophilia and was diagnosed in 11 (10.7%) patients (compared with 7% prevalence in the general population). The prevalence of all thrombophilias (except prothrombin mutation) was significantly higher in patients with PMPC in comparison with the reported prevalence in the general population. CONCLUSION: The incidence of thrombophilia was higher in patients with PMPC than in the general population. A positive thrombophilia diagnosis in a patient with PMPC can have significant clinical consequences for future pregnancies. It can also instigate thrombophilia testing among a patient's family members if necessary. Owing to these advantages, continued thrombophilia testing in these patients seems appropriate.

A Population-Based Study of Cholesterol Measurements in the Oldest Old.

BACKGROUND: Effect of lipid-lowering treatment in the oldest old is a matter of debate as there is no unequivocal evidence of statins being beneficial among the oldest. The need for cholesterol measurements is therefore also questionable, but the frequency of cholesterol measurements in the oldest old has not been described on a population basis. Therefore, the number of lipid measurements in the period 2002-2012 was evaluated for people aged 85+ years. METHODS: The Laboratory Information System and the Population Register at Statistics Denmark were used for retrieving data on people aged 85+ living on the Island of Funen. The development in trends for cholesterol measurements was analysed in age groups of 5-years interval using linear regression analysis. RESULTS: A total of 30,424 persons with a cholesterol measurement entered the study. The total number of cholesterol measurements increased by 246% during the observation period. The percentage of people having a cholesterol measurement increased significantly (p < 0.001) from 2002 to 2012 for all groups except males over 100 years of age. The increase was only due to requests from general practitioners, not from hospital units. CONCLUSION: Despite the uncertainty regarding lipid-lowering treatment in the oldest old, the percentage of people having a cholesterol measurement increased significantly during the study period. Whether this increase in cholesterol measurements leads to increased prescription of lipid-lowering medication in this cohort and/or better outcomes warrants future research.

NT-proBNP on Cobas h 232 in point-of-care testing: Performance in the primary health care versus in the hospital laboratory.

BACKGROUND: NT-proBNP may be useful for ruling out heart failure in primary health care. In this study we examined the analytical quality of NT-proBNP in primary health care on the Cobas h 232 point-of-care instrument compared with measurements performed in a hospital laboratory. MATERIALS AND METHODS: Blood samples requested for NT-proBNP were collected in primary health care (n = 95) and in a hospital laboratory (n = 107). NT-proBNP was measured on-site on Cobas h 232 instruments both in primary health care centres and at the hospital laboratory and all samples were also analyzed with a comparison method at the hospital. Precision, trueness, accuracy, and lot-variation were determined at different concentration levels and evaluated according to acceptance criteria. Furthermore user-friendliness was assessed by questionnaires. RESULTS: For Cobas h 232 repeatability CV was 8.5-10.7% in the hospital setting and 5.3-10.0% in the primary health care and within the analytical quality specifications, but higher than with the comparison method (< 4%). NT-proBNP results obtained in primary health care were significantly higher than by the hospital comparison method (bias ranged from 14.3-23.7%), whereas there was no significant bias when Cobas h 232 was used in the hospital setting (bias ranged from - 4.9 to 7.0%). User-friendliness of Cobas h 232 was overall acceptable. CONCLUSION: Cobas h 232 point-of-care instrument for measurement of NT-proBNP performed satisfactorily with regard to precision, user-friendliness, and lot-variation. A decrease in NT-proBNP levels observed in samples transported to a central laboratory needs further attention and investigation.

SearCh for humourIstic and Extravagant acroNyms and Thoroughly Inappropriate names For Important Clinical trials (SCIENTIFIC): qualitative and quantitative systematic study.

OBJECTIVES: To describe the development of acronym use across five major medical specialties and to evaluate the technical and aesthetic quality of the acronyms. DESIGN: Acronyms obtained through a literature search of Pubmed.gov followed by a standardised assessment of acronym quality (BEAUTY and CHEATING criteria). PARTICIPANTS: Randomised controlled trials within psychiatry, rheumatology, pulmonary medicine, endocrinology, and cardiology published between 2000 and 2012. MAIN OUTCOME MEASURES: Prevalence proportion of acronyms and composite quality score for acronyms over time. RESULTS: 14,965 publications were identified, of which 18.3% (n=2737) contained an acronym in the title. Acronym use was more common among cardiological studies than among the other four medical specialties (40% v 8-15% in 2012, P<0.001). Except for within cardiology, the prevalence of acronyms increased over time, with the average prevalence proportion among the remaining four specialties increasing from 4.0% to 12.4% from 2000 to 2012 (P<0.001). The median combined acronym quality score decreased significantly over the study period (P<0.001), from a median 9.25 in 2000 to 5.50 in 2012. CONCLUSION: From 2000 to 2012 the prevalence of acronyms in trial reports increased, coinciding with a substantial decrease in the technical and aesthetic quality of the acronyms. Strict enforcement of current guidelines on acronym construction by journal editors is necessary to ensure the proper use of acronyms in the future.

[Hypercoagulability in a patient with meningioma and Factor VLeiden mutation].

A 63-year-old woman with meningioma was admitted for surgery. Preoperatively she presented with a clinical state of hypercoagulability in the large central veins visualised by ultrasound. She had no previous history of thrombosis. Surgery was postponed and by biochemical evaluation only Factor VLeiden heterozygosity was found. Weeks later the patient was readmitted for surgery. No bleeding or thrombotic complications were experienced during the operation. The observed condition might be a result of a combination of the Factor VLeiden mutation and her meningioma. Meningioma itself has not been described as a risk factor of venous thrombosis.