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Testosterone (T), sex hormone binding globulin (SHBG), free testosterone (FT) and bioavailable testosterone (BAT) are commonly employed tests in pediatric endocrinology and all require age-dependent reference intervals for interpretation. The common methods used to derive these reference intervals require decisions about data shape and/or age partition thresholds, which can result in sharp differences between age groups, particularly for pubescent children. Partitioning also results in a form of data loss, where data from one age-bin is completed disconnected from the adjacent age-bins. Non-parametric continuous reference intervals methods have previously been developed to avoid some of these drawbacks. These strategies use all the available data and smooth transitions between ages avoiding partitioning. However, the fitting process involves selection and adjustment of many parameters and it can be difficult to maintain a reproducible approach. Here we provide a workflow for non-parametric continuous reference intervals applied to T, FT, BAT, and SHBG using the R language quantregGrowth package. T measurements were determined by LC-MS/MS, FT and BAT were calculated, and SHBG was measured on the Roche Cobas e601. The continuous interval methodology is described in detail with code examples and illustrations for reproducibility.

Background and Purpose: Elevation of total protein level in cerebrospinal fluid (CSF-TP) in diabetic patients is often disregarded by clinicians. However, existing studies on the topic have significant limitations, and therefore we aimed to explore the relationship between diabetes and CSF-TP in a large database of CSF samples. Methods: Retrospective review of all diagnostic lumbar punctures at the Ottawa Hospital between 1996-2016. Patients were excluded if they had elevated CSF cell counts, or a condition known to elevate CSF-TP. Multivariate linear regression modeling considered the effects of age, sex, and diabetes. Results: Among 6124 patients (746 with diabetes, 5378 without), mean CSF-TP did not differ significantly between groups (0.39 and 0.35 mmol/L, p = 0.2). When controlled for age and sex, there was no significant effect of diabetes on CSF-TP and no significant correlation between mean serum glucose and CSF-TP (R2 = 0.12). Conclusions: CSF-TP did not differ significantly between diabetic and non-diabetic groups, once the influence of age and sex was controlled. Elevated CSF-TP should be regarded as pathologic, even in the setting of diabetes.

Context.— The process for identifying patients with monoclonal gammopathies is complex. Initial detection of a monoclonal immunoglobulin protein (M protein) in the serum or urine often requires compilation of analytical data from several areas of the laboratory. The detection of M proteins depends on adequacy of the sample provided, available clinical information, and the laboratory tests used. Objective.— To develop an evidence-based guideline for the initial laboratory detection of M proteins. Design.— To develop evidence-based recommendations, the College of American Pathologists convened a panel of experts in the diagnosis and treatment of monoclonal gammopathies and the laboratory procedures used for the initial detection of M proteins. The panel conducted a systematic literature review to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, recommendations were created based on the available evidence, strength of that evidence, and key judgements as defined in the Grading of Recommendations Assessment, Development, and Evaluation Evidence to Decision framework. Results.— Nine guideline statements were established to optimize sample selection and testing for the initial detection and quantitative measurement of M proteins used to diagnose monoclonal gammopathies. Conclusions.— This guideline was constructed to harmonize and strengthen the initial detection of an M protein in patients displaying symptoms or laboratory features of a monoclonal gammopathy. It endorses more comprehensive initial testing when there is suspicion of amyloid light chain amyloidosis or neuropathies, such as POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome, associated with an M protein.

Background Parathyroid hormone (PTH) is measured routinely as part of Chronic Kidney Disease Bone and Mineral Disorders (CKD-MBD) assessment. Multiple PTH assays exist with known differences resulting in CKD-MBD guidelines recommending treatment based on assay-specific thresholds. The study objectives are to assess between manufacturer and within manufacturer variability of PTH assays and the impact of assay variability on the assessment of CKD-BMD using both vendor defined and empirically derived thresholds. Methods Data were collected from Ontario, Canada’s Proficiency Testing Program (24 challenge vials, 115–133 laboratories all using secondary generation PTH assays. Mean PTH and precision by the coefficient of analytical variation (CVa) were calculated. For each vial, whether the manufacturer’s mean value exceeded the vendor-defined and empirically-derived upper limit of normal (ULN) was recorded and the concordance between assays was determined. Results Across all laboratories, the mean PTH range was 12.0 ± 3.9 pmol/L and the mean CVa was 30%. The percent of vials with a mean PTH exceeding manufacturer’s specific ULN varied substantially between manufacturers. Only 58% of vials had complete concordance as to whether mean PTH was above assay-specific ULNs. This increased to 83% using the empirically derived ULN. Conclusions CKD-BMD assessment and management will depend on the PTH assay. The between-assay variability is reduced but not eliminated when empirically derived reference intervals are used. Improvements in PTH measurement are required in order to ensure consistent patient care.

Several small studies have identified possible associations between low serum zinc levels and worse outcomes in patients acutely hospitalized for a variety of diseases. This study systematically evaluated all published literature to determine whether serum zinc might independently predict important outcomes in hospitalized patients. PubMed, Embase, and Cochrane Libraries databases were searched from 1970 to 2019 to identify all citations having the keyword “zinc” with hospital outcomes. Studies were included if they measured the association between serum zinc levels in non-electively hospitalized patients with survival, length of stay, or unplanned readmission. Data were double-abstracted to evaluate the association between zinc levels and these outcomes. Our search returned 1091 citations of which 12 studies met the inclusion criteria. Studies were small (median 112.5 patients) using unspecified sampling methods. Seven studies were restricted to critically ill patients. Mean zinc levels ranged from 27.5 to 85.3 μg/dL. Baseline mean zinc levels were significantly lower (p < 0.05) in patients who eventually died in 1 of 7 studies. Five of seven studies found significantly increased risk of death in hospital with lower zinc levels. Associations between zinc levels and critical care or hospital length of stay were unclear. In 1 study, lower zinc levels were associated with a significantly increased risk of unplanned readmission. Current studies measuring the association between serum zinc levels and outcomes in acutely hospitalized patients are limited by their sample sizes, select patient populations, and limited statistical analyses. The association of zinc levels with hospital patient outcomes is unclear.

Introduction N-acetylcysteine (NAC) is an antioxidant that can regenerate glutathione and is primarily used for acetaminophen overdose. NAC has been tested and used for preventing iatrogenic acute kidney injury or slowing the progression of chronic kidney disease, with mixed results. There are conflicting reports that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, we conducted a systematic review of the literature to determine whether there is an effect of NAC on kidney function as measured with serum creatinine and cystatin C. Methods A literature search was conducted to identify all study types reporting a change in serum creatinine after NAC administration. The primary outcome was change in serum creatinine after NAC administration. The secondary outcome was a change in cystatin C after NAC administration. Subgroup analyses were conducted to assess effect of creatinine assay (Jaffe vs. non-Jaffe and intravenous vs. oral). Results Six studies with a total of 199 participants were eligible for the systematic review and meta-analysis. There was a small but significant decrease in serum creatinine after NAC administration overall (weighted mean difference [WMD], −2.80 μmol/L [95% confidence interval {CI} −5.6 to 0.0]; P = 0.05). This was greater with non-Jaffe methods (WMD, −3.24 μmol/L [95% CI −6.29 to −0.28]; P = 0.04) than Jaffe (WMD, −0.51 μmol/L [95% CI −7.56 to 6.53]; P = 0.89) and in particular with intravenous (WMD, −31.10 μmol/L [95% CI −58.37 to −3.83]; P = 0.03) compared with oral NAC (WMD, −2.5 μmol/L [95% CI −5.32 to 0.32]; P = 0.08). There was no change in cystatin C after NAC administration. Discussion NAC causes a decrease in serum creatinine but not in cystatin C, suggesting analytic interference rather than an effect on kidney function. Supporting this, the effect was greater with non-Jaffe methods of creatinine estimation. Future studies of NAC should use the Jaffe method of creatinine estimation when kidney outcomes are being reported. Even in clinical settings, the use of an enzymatic assay when high doses of intravenous NAC are being used may result in underdiagnosis or delayed diagnosis of acute kidney injury., Graphical abstract

Background Commonly used estimated glomerular filtration rate (eGFR) equations include a Black race modifier (BRM) that was incorporated during equation derivation. Race is a social construct, and a poorly characterized variable that is applied inconsistently in clinical settings. The BRM results in higher eGFR for any creatinine concentration, implying fundamental differences in creatinine production or excretion in Black individuals compared to other populations. Equations without inclusion of the BRM have the potential to detect kidney disease earlier in patients at the greatest risk of chronic kidney disease (CKD), but also has the potential to over-diagnose CKD or impact downstream clinical interventions. The purpose of this study was to use an evidence-based approach to systematically evaluate the literature relevant to the performance of the eGFR equations with and without the BRM and to examine the clinical impact of the use or removal. Content PubMed and Embase databases were searched for studies comparing measured GFR to eGFR in racially diverse adult populations using the Modification of Diet in Renal Disease or the 2009-Chronic Kidney Disease Epidemiology Collaboration-creatinine equations based on standardized creatinine measurements. Additionally, we searched for studies comparing clinical use of eGFR calculated with and without the BRM. Here, 8632 unique publications were identified; an additional 3 studies were added post hoc. In total, 96 studies were subjected to further analysis and 44 studies were used to make a final assessment. Summary There is limited published evidence to support the use of a BRM in eGFR equations.

KEY POINTS A 53-year-old woman was referred to the endocrinology clinic for recurrent hypoglycemia detected on blood-work. The patient’s fasting serum glucose values over the previous year ranged from 2.6 to 3.4 mmol/L. Although asymptomatic, she was given juice as treatment each time the result

Reference intervals have traditionally been partitioned by age based on statistical significance and physiological relevance. However, analyte concentration does not change abruptly with age, but rather dynamically. In this study, we establish biochemical marker continuous reference intervals for a Canadian population using healthy pediatric reference individuals and compare these to partitioned reference intervals.Continuous reference intervals spanning 1-18.5 years of age were established using data from healthy CALIPER children and adolescents aged 6 months- 19 years. Continuous reference intervals (i.e. 2.5th and 97.5th quantiles) were generated by nonparametric quantile regression via penalized splines with non-crossing constraints. Abnormal flagging rates of established continuous reference intervals were compared to previously established age-partitioned CALIPER reference intervals for five biochemical markers using internal (CALIPER) and external (i.e. Canadian Health Measures Survey (CHMS)) datasets.Continuous reference intervals were determined for 38 biochemical markers, with 21 markers requiring sex-specific reference intervals. Despite similar total flagging rates to partitioned reference intervals, continuous reference intervals appeared to provide a more consistent and accurate estimation of reference limits for biomarkers with more complex age-related changes, including alkaline phosphatase and phosphate.This is the first report of continuous biochemical marker reference intervals based on a healthy Canadian pediatric population. Reference limit point estimates based on continuous reference intervals are provided to aid clinical implementation. Continuous reference intervals offer a better estimation of dynamic changes in biochemical marker reference values with age, resulting in improved laboratory test result interpretation and clinical decision making in pediatrics.

Background:The antiquated standard reference range of 0.15–0.45 g/L for cerebrospinal fluid total protein (CSF-TP) is well entrenched in medical literature and laboratory operating procedures across the world.Methods:We conducted a web-based survey with a response rate of 34.9% through the listserv of the Canadian Neurological Sciences Federation. Additional laboratory reference data were collated by telephone interview of hospital laboratory technologists across Canada.Results:A total of 142 site responses were obtained: 64.1% from academic/tertiary hospitals and 35.9% from community hospitals. A strong majority (80.4%) of both types of institutions reported using a CSF-TP upper reference limit of 0.45 g/L or less. As a rule, no age adjustments were implemented in CSF-TP-level interpretation.Conclusions:Recent well-powered laboratory reference studies have documented CSF-TP upper reference limits that are above 0.6 g/L starting at age 50, with incremental limits partitioned by subsequent decades of age. The conventional 0.45 g/L limit could lead to false positive results. Our survey suggests there is a need to consider a wide adoption of data-driven, rather than historical, reference values.

Background Artificial intelligence (AI) is rapidly being developed and implemented to augment and automate decision-making across healthcare systems. Being an essential part of these systems, laboratories will see significant growth in AI applications for the foreseeable future. Content In laboratory medicine, AI can be used for operational decision-making and automating or augmenting human-based workflows. Specific applications include instrument automation, error detection, forecasting, result interpretation, test utilization, genomics, and image analysis. If not doing so today, clinical laboratories will be using AI routinely in the future, therefore, laboratory experts should understand their potential role in this new area and the opportunities for AI technologies. The roles of laboratorians range from passive provision of data to fuel algorithms to developing entirely new algorithms, with subject matter expertise as a perfect fit in the middle. The technical development of algorithms is only a part of the overall picture, where the type, availability, and quality of data are at least as important. Implementation of AI algorithms also offers technical and usability challenges that need to be understood to be successful. Finally, as AI algorithms continue to become available, it is important to understand how to evaluate their validity and utility in the real world. Summary This review provides an overview of what AI is, examples of how it is currently being used in laboratory medicine, different ways for laboratorians to get involved in algorithm development, and key considerations for AI algorithm implementation and critical evaluation.

Objectives The value of the serum protein gap (PG, difference between total protein and albumin) in the detection of hyper- or hypogammaglobulinemia is not well established. We assessed the performance of PG for the detection of hyper- or hypogammaglobulinemia in a large sample of patients. Methods We reviewed all paired measurements of serum total protein, albumin, quantitative immunoglobulins, and serum protein electrophoresis tested between March 2014 and June 2017 at the Eastern Ontario Regional Laboratory Association. Sensitivity, specificity, positive predictive value, negative predictive value and likelihood ratios of PG at thresholds between 18 and 44 g/L for the detection of hyper- and hypogammaglobulinemia were assessed. Results There were 19,575 and 5,426 simultaneous paired data points to assess hyper- and hypogammaglobulinemia identified by serum protein electrophoresis (SPE) and nephelometry, respectively. The mean PG was 36.3 g/L (SD 8.6). The prevalence of hypergammaglobulinemia (>16 g/L by SPE) and hypogammaglobulinemia (IgG Conclusions High and low PG values were not sensitive in detecting hyper- or hypogammaglobulinemia, although negative predictive values were high for both. Performance of PG should be further evaluated prospectively in specific populations at risk of for abnormal IgG levels.

Objectives Point-of-care testing (POCT) is testing performed outside the traditional laboratory, often at the patient bedside. In hospital settings, blood glucose is the most common POCT. Staff performing POCT are not usually laboratory trained; they are clinical staff with a primary focus on treating patients. Clinical staff find POCT quality assurance (QA) practices burdensome and are often non-compliant. In hospitals within EORLA (Eastern Ontario Regional Laboratories Association), all critically high POCT glucose results must be repeated prior to acting, according to policy. Compliance with this policy is audited regularly. Design and methods: All POCT glucose tests performed in participating sites between January and June 2018 and June and December 2019 were audited for compliance with the critical repeat policy. The discordant repeat rate was also determined for each audit period. Between January and May 2019, there were interventions aimed at improving compliance with the repeat policy. Results Compliance with the critical repeat policy increased from 30 to 57% in 2019 compared to 2018, following nursing education and implementation of notifications on the glucose meters themselves. The rate of discordant repeat results (>20% different from initial) also improved at most sites in 2019 compared to 2018. Nurses cited insufficient cleaning of patient hands prior to initial testing as the primary reason for discordant repeats. Conclusions Operator compliance with POCT QA policies is an ongoing challenge requiring continual audit, feedback and education. A strong POCT multi-disciplinary committee with supports from senior and clinical leadership in an organization are key to improving compliance., Highlights • Compliance with the policy requiring repeat of all critically high POCT glucose results is audited as a quality indicator. • Audits demonstrated a high rate of non-compliance with the critical repeat policy by clinical staff performing POCT. • Approximately 25% of critically high glucose results repeated were discordant (>20% different from the initial result) • Implementation of meter notifications and nursing education led to significant improvements in compliance at most sites.

Cerebrospinal fluid total protein (CSF-TP) is measured in the diagnosis of a range of immune or infectious disorders of the nervous system. Most laboratories and the medical literature use an antiquated, age-independent upper limit of 0.45 g/L. Therefore, we performed a systematic review of reference studies in the medical literature, with the primary objective of determining the CSF total protein upper reference limit (URL). Secondary objectives were to assess the effects of age, gender, laboratory methods, and methodological quality. A pre-planned and peer-reviewed electronic search strategy was used to search Ovid Medline and EMBASE for 1960–2017. All records underwent title/abstract review, and potentially relevant records underwent independent full-text review by two researchers. The remaining studies underwent quality assessment using a modification of the QUADAS2 revised tool. CSF-TP upper reference limits extracted from these studies were used to compute weighted means. Twenty-two articles were retained for qualitative analysis and 20 for quantitative analysis. The weighted average of CSF-TP URL was 0.55 g/L, in studies with high methodological quality. Studies that examined the effect of age reported consistent correlations with advancing age, and CSF-TP URL values incrementally exceeded 0.60 g/L after age 50. There were no meaningful differences according to gender, laboratory method, or quality assessment score. There is concordance in available literature to recommend increasing CSF total protein upper reference limits, and to consider implementing age-adjusted values above 0.60 g/L starting at age 50. This information merits worldwide dissemination, to reduce the risk of over-diagnosis.

Metformin-associated lactic acidosis [MALA] is a potentially fatal condition characterized by an elevation in serum lactate in patients with metformin exposure. An 82-year-old man with no prior renal history was brought to hospital after being found by his family in a confused state. He had a history of type 2 diabetes mellitus, and his medications included regular metformin. On arrival to our hospital he was conscious but confused and noted recent decreased oral intake. Initial investigations revealed severe acidemia (pH

Protein electrophoresis is commonly used as an aid in the diagnosis of monoclonal gammopathies and is performed in many laboratories in Canada and throughout the world. However, unlike many other diagnostic tests, there is limited guidance for standardization and neither guidance nor specific recommendations for clinical reporting of serum (SPE) or urine (UPE) protein electrophoresis and immunotyping available in the literature. Therefore, a Canadian effort was undertaken to recommend standards that cover all aspects of clinical reporting with an ultimate goal towards reporting standardization. The Canadian Society of Clinical Chemists (CSCC) Monoclonal Gammopathy Interest Group (MGIG), which is composed of CSCC members with an interest in protein electrophoresis, has formed a Monoclonal Gammopathy Working Group (MGWG) to take initial steps towards standardization of SPE, UPE and immunotyping. Candidate standardization recommendations were developed, discussed and voted upon by the MGWG. Candidate recommendations that achieved 90% agreement are presented as consensus recommendations. Recommendations that did not achieve 90% consensus remain candidate recommendations and are presented with accompanying MGWG discussion. Eleven consensus recommendations along with candidate recommendations for nomenclature, protein fraction reporting, test utilization, interference handling and interpretive reporting options are presented.

BACKGROUND Reference intervals are vital for interpretation of laboratory results. Many existing reference intervals for cerebrospinal fluid total protein (CSF-TP) are derived from old literature because of the invasive nature of sampling. The objective of this study was to determine reference intervals for CSF-TP using available patient data. METHODS Twenty years of hospital database information was mined for previously reported CSF-TP results. Associated demographic, laboratory, and clinical diagnosis (International Classification of Diseases 9/10 codes) details were extracted. CSF-TP results included 3 different analytical platforms: the Siemens Vista 1500, Beckman Lx20, and Roche Hitachi 917. From an initial data set of 19591 samples, the following exclusion criteria were applied: incomplete data, white blood cells (WBCs) >5 × 106/L, red blood cells (RBCs) >50 × 106/L, and glucose RESULTS CSF-TP showed a marked age dependence, and males had significantly higher CSF-TP than females across all ages. CSF-TP results from the 3 different instruments and manufacturers showed small (approximately 0.04 g/L), but statistically significant, differences. CSF-TP showed weak, but again statistically significant, correlation with WBC and RBC but was independent of serum total protein and creatinine. CONCLUSIONS The age dependence of CSF-TP supports that age-partitioned reference intervals will be more accurate than a single cutoff, particularly in patients with advancing age.

Pregnancy is a normal condition that begins at conception, which is defined as fertilization of a mature ovum with sperm produced by functional female and male reproductive systems. Maternal and fetal physiologies are tightly regulated during pregnancy. Disruption in this regulation leads to abnormalities in the mother and/or fetus. Analytes detected in maternal serum and amniotic fluid can monitor normal and abnormal pregnancies and predict outcome of fetal anomalies.

Analgesic and anti-inflammatory drugs are a broad category of compounds that are used to treat swelling, redness, and pain. They are the most widely used drugs in the world. It is estimated that some 7 billion grams of acetaminophen alone is consumed in the United States each year, with over 60 million individuals using the drug on a weekly basis. Analgesic and anti-inflammatory drugs are available both over-the-counter at low doses and by prescription at higher doses. They are available as monotherapy and in combination with numerous other compounds for the treatment of conditions such as flu, aches, pains, and fever.

The reproductive system is regulated by hormones produced by the hypothalamic–pituitary–gonadal (HPG) axis and adrenal glands. Hormones from these systems control development of the male and female reproductive systems and maintain sexual and reproductive function after onset of puberty. Dysregulation of one or more of these hormones may result in reproductive dysfunction and infertility. Diagnosis and monitoring of reproductive disorders hinges on measurement of hormones produced by the HPG axis or adrenal glands.

Laboratory data account for approximately 70% of the information in a patient’s medical record. This information is underpinned by a host of technical and regulatory requirements, system architecture, and security controls. At the digital heart of most laboratories are laboratory information systems (LIS). LIS receive test requests and patient demographics from admission, discharge, and transfer systems and transmit it to analytical instrumentation. Instrumentation returns result to LIS, which in turn transmits results back to clinical viewers, such that healthcare providers can make decisions. To achieve this transmission to and from the LIS, there are needs for data encoding standards, such as Health Level 7 messages. Outside of the LIS, there is also information relevant to the testing process, such as document management, quality control, and semistructured data. By harnessing all these data, laboratories have numerous opportunities to increase operational efficiency, improve quality, and perform research.

Background Serum protein electrophoresis (SPEP) is used to quantify the serum monoclonal component or M-protein, for diagnosis and monitoring of monoclonal gammopathies. Significant imprecision and inaccuracy pose challenges in reporting small M-proteins. Using therapeutic monoclonal antibody-spiked sera and a pooled beta-migrating M-protein, we aimed to assess SPEP limitations and variability across 16 laboratories in three continents. Methods Sera with normal, hypo- or hypergammaglobulinemia were spiked with daratumumab, Dara (cathodal migrating), or elotuzumab, Elo (central-gamma migrating), with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Provided with total protein (reverse biuret, Siemens), laboratories blindly analyzed samples according to their SPEP and immunofixation (IFE) or immunosubtraction (ISUB) standard operating procedures. Sixteen laboratories reported the perpendicular drop (PD) method of gating the M-protein, while 10 used tangent skimming (TS). A mean percent recovery range of 80%–120% was set as acceptable. The inter-laboratory %CV was calculated. Results Gamma globulin background, migration pattern and concentration all affect the precision and accuracy of quantifying M-proteins by SPEP. As the background increases, imprecision increases and accuracy decreases leading to overestimation of M-protein quantitation especially evident in hypergamma samples, and more prominent with PD. Cathodal migrating M-proteins were associated with less imprecision and higher accuracy compared to central-gamma migrating M-proteins, which is attributed to the increased gamma background contribution in M-proteins migrating in the middle of the gamma fraction. There is greater imprecision and loss of accuracy at lower M-protein concentrations. Conclusions This study suggests that quantifying exceedingly low concentrations of M-proteins, although possible, may not yield adequate accuracy and precision between laboratories.

Background Electrophoretic methods to detect, characterize and quantify M-proteins play an important role in the management of patients with monoclonal gammopathies (MGs). Significant uncertainty in the quantification and limit of detection (LOD) is documented when M-proteins are Methods Sera with normal, hypo- or hyper-gammaglobulinemia were spiked with daratumumab or elotuzumab, with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Laboratories blindly analyzed samples according to their serum protein electrophoresis (SPEP)/isotyping standard operating procedures. LOD and intra-laboratory percent coefficient of variation (%CV) were calculated and further specified with regard to the method (gel/capillary electrophoresis [CZE]), gating strategy (perpendicular drop [PD]/tangent skimming [TS]), isotyping (immunofixation/immunosubtraction [ISUB]) and manufacturer (Helena/Sebia). Results All M-proteins ≥1 g/L were detected by SPEP. With isotyping the LOD was moderately more sensitive than with SPEP. The intensity of polyclonal background had the biggest negative impact on LOD. Independent of the method used, the intra-laboratory imprecision of M-protein quantification was small (mean CV = 5.0%). Low M-protein concentration and high polyclonal background had the strongest negative impact on intra-laboratory precision. All laboratories were able to follow trend of M-protein concentrations down to 1 g/L. Conclusions In this study, we describe a large variation in the reported LOD for both SPEP and isotyping; overall LOD is most affected by the polyclonal immunoglobulin background. Satisfactory intra-laboratory precision was demonstrated. This indicates that the quantification of small M-proteins to monitor patients over time is appropriate, when subsequent testing is performed within the same laboratory.

Context Calculated non–high-density lipoprotein (HDL) cholesterol (non-HDLC) should selectively include cholesterol from atherogenic lipoproteins to be a reliable risk marker of cardiovascular disease. In hypertriglyceridemia (HTG), there is increased abundance of larger and less atherogenic triglyceride-rich lipoproteins (TRL), namely, larger very-low-density lipoproteins (VLDL), and chylomicrons. Objective We aim to demonstrate that serum triglyceride (TG) level has a substantial impact on non-HDLC’s ability to represent cholesterol from atherogenic lipoproteins, even though TG is not part of the calculation for non-HDLC. Design Analysis of lipid profile data Settings Lipid Clinic patient cohort, and Biochemistry Laboratory patient cohort Patients or Other Participants 7,492 patients in the Lipid Clinic cohort with baseline lipid profiles documented prior to starting lipid-lowering medications and 156,311 lipid profiles from The Ottawa Hospital Biochemistry Laboratory cohort. Intervention None Main Outcome Measure Our modeling process includes derivation of TG-interval–specific lipoprotein composition factor (LCF) for TRL, which represents the mass ratio of cholesterol to TG in TRL. A high LCF indicates that the TRLs are mainly the cholesterol-rich atherogenic remnant lipoproteins. A low LCF indicates that the TRLs are mainly the TG-rich larger VLDL and chylomicrons. Results As serum TG increases, there is progressive decline in the LCF for TRL, which indicates that the calculated non-HDLC level reflects progressive inclusion of cholesterol from larger TRL. This is shown in both cohorts. Conclusions Calculated non-HDLC is influenced by TG level. As TG increases, non-HDLC gradually includes more cholesterol from larger TRL, which are less atherogenic than LDL and remnant lipoproteins.

Background Zinc deficiency is easily treated and has been associated with worse outcomes in hospitalized patients. Zinc testing is time-consuming and relatively costly. We identified every zinc level measured at our teaching hospital and quantified how much zinc variation is explained by other hospital factors. Methods We linked tables from our hospital data warehouse from 1996 to 2019 to identify all patients who had at least 1 serum zinc measured during their admission. We determined the status of factors that could influence zinc levels including severity of illness, presence of bleeding or inflammation, and factors influencing zinc absorption. Results We identified only 318 adult patients having zinc measurement during their hospitalization. Patients were elderly (median age 71 [IQR 56–78]) and arrived by ambulance 45% of the time. Zinc was measured a median of 5 days into the hospitalization (IQR 3–13) with 154 (51.6%) recording a low level. Almost half of patients were missing at least one covariable laboratory test. Multilinear regression models using complete case analysis returned more extreme parameter estimate values and deemed as significant only two thirds of the factors identified as significant in models using data with missing values imputed. Imputed models found significant associations between lower zinc levels and recent surgery, decreased albumin, creatinine, and sodium, earlier hospitalization day of sampling, and increased patient comorbidity. These models explained 32% of zinc variation. Conclusions Zinc testing is rare, low zinc levels are very common, and one third of its variation in hospitalized patients is explained by other covariables.

Background The cerebrospinal fluid total protein level (CSF-TP) is commonly used as a potential marker of infectious or immune disease of the CNS and PNS. Recent laboratory reference studies indicate that the antiquated single upper reference limit of 0.45 g/L commonly used by hospital laboratories and widely quoted in medical literature is a significant underestimation. Methods We distributed worldwide a web-based survey comprised of three questions: 1. What is the CSF-TP upper limit used at your institution? 2. What is the source of this upper limit? 3. Do you adjust your upper limit according to age? Results A total of 473 unique responses were obtained from North America (37.5%), South America (5.5%), Europe (29.4%), Africa (4%), Asia (21.6%) and Oceania (1.7%). A strong preponderance (86.8%) of institutions reported an upper limit of 0.45 g/L or less. Only 4% reported making age-partitioned adjustments. Conclusions Worldwide, a strong majority of hospital laboratories presently use an underestimation of CSF-TP upper reference value, particularly for older adults. Recent well powered laboratory reference studies support higher values with age adjustment.

N-acetylcysteine (NAC) is an antioxidant which can regenerate glutathione and is primarily used for acetaminophen overdose. It is also a potential therapy to prevent iatrogenic acute kidney injury or slow the progression of chronic kidney disease. It has been considered in this context by many studies with mixed results. Notably, a biological-mechanism rationale for a protective effect of NAC has never been adequately reported. Among conflicting reports, there appears to be evidence that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, a systematic review of the literature will be conducted to determine whether there is an effect of NAC on kidney function measured with serum creatinine.To determine the effect of NAC on kidney function.A systematic review and meta-analysis.Prospective studies, with administration of NAC, in the absence of any other change in kidney function (such as contrast administration or surgery).Adult humans aged 18 years old or more, either healthy volunteers or with chronic kidney disease, were administered with NAC. Populations having little to no kidney function such as in end-stage kidney disease will be excluded.Serum creatinine and/or cystatin C measurements before and after NAC administration.An information specialist will assist in searching MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify all study types including randomized controlled trials, and prospective cohort studies reporting change in serum creatinine after NAC administration. Two reviewers will independently screen the titles and abstracts of the studies obtained from the search using predefined inclusion criteria and will then extract data from the full texts of selected studies. The weighted mean difference will be calculated for change in creatinine with NAC, using random-effects analysis. Quality assessment will be done with the Cochrane Risk of Bias tool for randomized trials and the Newcastle-Ottawa Scale for observational studies.The outcome of interest is kidney function as reported by either change in serum creatinine and/or serum cystatin C measurement for randomized trials or comparing baseline (pre-NAC dose) values and those following the NAC dose.Possible heterogeneity and publication bias and lack of mechanistic data.This systematic review will provide a synthesis of current evidence on the effect of NAC on serum creatinine measurement. These findings will provide clinicians with guidelines and serve as a strong research base for future studies in this field.This review is registered with PROSPERO, CRD42017055984.La N-acétylcystéine (NAC) est un antioxydant capable de régénérer le glutathion et principalement utilisé pour traiter les cas de surdose d’acétaminophène. La NAC pourrait également s’avérer efficace comme traitement préventif de l’insuffisance rénale aiguë iatrogénique ou pour ralentir la progression de l’insuffisance rénale chronique. Cette substance a fait l’objet de plusieurs études dans ce contexte, mais les résultats demeurent mitigés. Notamment, il reste toujours à rapporter adéquatement une justification de l’effet protecteur de la NAC sur la base d’un mécanisme biologique. Parmi les rapports contradictoires, certaines données montreraient que la NAC abaisse artificiellement les valeurs de créatinine sérique mesurées sans améliorer la fonction rénale, potentiellement par interférence de l’essai. À la lumière de ces résultats divergents, une revue systématique de la littérature sera effectuée pour déterminer si la NAC produit un effet sur la fonction rénale mesurée par la créatinine sérique.Mesurer l’effet de l’administration de NAC sur la fonction rénale.Une revue systématique de la littérature et une méta-analyse.Les études prospectives avec administration de NAC sans autres changements dans la fonction rénale; l’administration d’un produit de contraste ou une intervention chirurgicale, par exemple.Des adultes, volontaires sains ou atteints de néphropathie chronique, ayant reçu de la NAC. Seront exclues les populations dont la fonction rénale est faible ou inexistante; notamment, les cas d’insuffisance rénale terminale.Des mesures de la créatinine sérique et/ou de la cystatine C faites avant et après l’administration de NAC.Un documentariste spécialisé assistera les recherches dans les bases de données MEDLINE, EMBASE et Cochrane CENTRAL afin de répertorier tous les types d’essais, y compris les essais contrôlés à répartition aléatoire, et toutes les études de cohorte prospectives faisant état d’une variation de la créatinine sérique à la suite de l’administration de NAC. À l’aide de critères d’inclusion prédéfinis, deux réviseurs seront indépendamment chargés de trier les titres et abrégés des études répertoriées lors de la revue de la littérature. Ils devront ensuite extraire les données des textes des études qui auront été retenues. Une analyse des effets aléatoires sera utilisée pour calculer la moyenne pondérée des écarts pour les variations observées dans les mesures de créatinine en présence de NAC. La qualité des essais aléatoires sera évaluée à l’aide de l’outil Cochrane sur le risque de biais, et celle des études observationnelles sera mesurée avec l’échelle de Newcastle-Ottawa.Le principal résultat d’intérêt est la fonction rénale telle que rapportée soit par un changement dans les mesures de créatinine sérique et/ou de la cystatine C dans les essais à répartition aléatoire, soit en comparant les valeurs mesurées avant et après l’administration d’une dose de NAC.L’hétérogénéité des données, de possibles biais de publication et un manque de données mécanistiques.Cette revue systématique offrira une synthèse des données probantes actuelles sur l’effet de la NAC sur les mesures de créatinine sérique. Ces résultats fourniront des lignes directrices aux cliniciens et serviront de bases solides pour les recherches futures dans ce domaine.

Therapeutic drug monitoring (TDM) is used to manage drugs with a narrow window between effective and toxic concentrations. TDM involves measuring blood concentrations of drugs to ensure effective therapy, avoid toxicity and monitor compliance. Common drugs for which TDM is used include aminoglycosides for infections, anticonvulsants to treat seizures, immunosuppressants for transplant patients and cardiac glycosides to regulate cardiac output and heart rate. An essential element of TDM is the provision of accurate and clinically relevant reference intervals. Unlike most laboratory reference intervals, which are derived from a healthy population, TDM reference intervals need to relate to clinical outcomes in the form of efficacy and toxicity. This makes TDM inherently more difficult to develop as healthy individuals are not on therapy, so there is no “normal value”. In addition, many of the aforementioned drugs are old and much of the information regarding reference intervals is based on small trials using methods that have changed. Furthermore, individuals have different pharmacokinetics and drug responses, particularly in the context of combined therapies, which exacerbates the challenge of universal TDM targets. This focused review examines the origins and limitations of existing TDM reference intervals for common drugs, providing targets where possible based on available guidelines.

Item does not contain fulltext Protein electrophoresis and immunofixation are subject to a variety of analytical interferences that may affect monoclonal protein diagnostics performed in the context of monoclonal gammopathies. Interferences include endogenous substances, such as hemoglobin and fibrinogen, and exogenous compounds, such as radiocontrast dyes, antibiotics, and monoclonal antibody therapies. General approaches to managing interferences begin with recognition of the problem. Provided herein are examples of common, rare, and novel interferences with the goal of providing a comprehensive overview. With each example, specific methods and strategies are provided to manage analytical interferences to ensure that interpretative reports are accurate. Longstanding and newer technologies are also described to contextualize where interferences may be identified and avoided.

Morbidity and Mortality Conferences (M&MCs) have for generations been part of the education of physicians, yet their effectiveness remains questionable. The Ottawa M&M Model (OM3) was developed to provide a structured approach to M&MCs in order to maximize the quality improvement impact of such rounds. We conducted a retrospective assessment of the impact of implementing nephrology-specific M&MCs using the OM3. All physicians, residents and fellows from the division of nephrology at a large academic medical center were invited to participate. Structured M&MCs were implemented to identify preventable errors and generate actions to improve quality of care and patient safety. Number and nature of cases reviewed, number and nature of recommendations generated through identification of preventable health system and/or cognitive factors. Morbidity and/or mortality in each case were identified. A determination of the underlying factors and preventability of these events was made. A qualitative review of resulting recommendations was performed. Over the course of sixteen 1-h long conferences, 52 cases were presented. For all cases presented, discussion, action items and information dissemination followed the OM3. As a result of the M&MCs, 29 recommendations (emanating from 27 cases) lead to improve care delivery. Limitations of this study include its retrospective nature and single-center design. The implementation of regularly scheduled M&MCs at an academic nephrology program, using a structured model, identified preventable health-systems issues and cognitive errors. Approximately one-half of the cases reviewed generated actions for health care delivery improvement.

The Kidney Failure Risk Equation (KFRE) predicts the need for dialysis or transplantation using age, sex, estimated glomerular filtration rate (eGFR), and urine albumin to creatinine ratio (ACR). The eGFR and ACR have known biological and analytical variability. We examined the effect of biological and analytical variability of eGFR and ACR on the 2-year KFRE predicted kidney failure probabilities using single measure and the average of repeat measures of simulated eGFR and ACR. Previously reported values for coefficient of variation (CV) for ACR and eGFR were used to calculate day to day variability. Variation was also examined with outpatient laboratory data from patients with an eGFR between 15 and 50 mL/min/1.72 m2. A web application was developed to calculate and model day to day variation in risk. The biological and analytical variability related to ACR and eGFR lead to variation in the predicted probability of kidney failure. A male patient age 50, ACR 30 mg/mmol and eGFR 25, had a day to day variation in risk of 7% (KFRE point estimate: 17%, variability range 14% to 21%). The addition of inter laboratory variation due to different instrumentation increased the variability to 9% (KFRE point estimate 17%, variability range 13% to 22%). Averaging of repeated measures of eGFR and ACR significantly decreased the variability (KFRE point estimate 17%, variability range 15% to 19%). These findings were consistent when using outpatient laboratory data which showed that most patients had a KFRE 2-year risk variability of ≤ 5% (79% of patients). Approximately 13% of patients had variability from 5-10% and 8% had variability > 10%. The mean age (SD) of this cohort was 64 (15) years, 36% were females, the mean (SD) eGFR was 32 (10) ml/min/1.73m2 and median (IQR) ACR was 22.7 (110). Biological and analytical variation intrinsic to the eGFR and ACR may lead to a substantial degree of variability that decreases with repeat measures. Use of a web application may help physicians and patients understand individual patient's risk variability and communicate risk (https://mccudden.shinyapps.io/kfre_app/). The web application allows the user to alter age, gender, eGFR, ACR, CV (for both eGFR and ACR) as well as units of measurements for ACR (g/mol versus mg/g).

The International Myeloma Working Group recommendations for monitoring disease progression or response include quantitation of the involved monoclonal immunoglobulin. They have defined the minimum change criteria of ≧25% with an absolute change of no5g/L for either minimal response or progression. Limited evidence is available to accurately determine the magnitude of change in a monoclonal protein to reflect a true change in clinical status. Here we determined the analytical and biological variability of monoclonal proteins in stable monoclonal gammopathy of undetermined significance (MGUS) patients.Analytical variability (CVa) of normal protein fractions and monoclonal proteins were assessed agarose gel-based serum protein electrophoresis. Sixteen clinically stable MGUS patients were identified from our clinical hematology database. Individual biological variability (CVi) was determined and used to calculate a monoclonal protein reference change value (RCV).Analytical variability of the normal protein fractions (albumin, alpha-1, alpha-2, beta, total gamma) ranged from 1.3% for albumin to 5.8% for the alpha-1 globulins. CVa of low (5.6g/L) and high (32.2g/L) concentration monoclonal proteins were 3.1% and 22.2%, respectively. Individual CVi of stable patients ranged from 3.5% to 24.5% with a CVi of 12.9%. The reference change value (RCV) at a 95% probability was determined to be 36.7% (low) 39.6% (high) using our CVa and CVi.Serial monitoring of monoclonal protein concentration is important for MGUS and multiple myeloma patients. Accurate criteria for interpreting a change in monoclonal protein concentration are required for appropriate decision making. We used QC results and real-world conditions to assess imprecision of serum protein fractions including low and high monoclonal protein fractions and clinically stable MGUS patients to determine CVi and RCV. The calculated RCVs of 36.7% (low) and 39.6% (high) in this study were greater that reported previously and greater than the established criteria for relapse. Response criteria may be reassessed to increase sensitivity and specificity for detection of response.

ObjectiveWe conducted a retrospective review of patients with a diagnosis of Guillain-Barré syndrome (GBS) to assess the diagnostic impact of applying age-adjusted upper limits for CSF total protein (CSF-TP) supported by a systematic literature review.MethodsCases coded as GBS or inflammatory neuropathy for the period 2001–2016 at The Ottawa Hospital were reviewed. Cases were included if they met the Brighton criteria for GBS with a diagnostic certainty level 1 or 2 and had contemporaneous CSF-TP data. We excluded cases with CSF pleocytosis >50 and cases with Miller-Fisher syndrome. Age-adjusted reference limits were compared with conventional 0.45 and 0.6 g/L upper limits.ResultsOne hundred thirty-eight cases met the study criteria, with a mean age of 47 years. The mean interval from symptom onset to lumbar puncture was 7.9 days, and mean CSF-TP was 1.23 g/L. There was a strong correlation between rising CSF-TP and time to lumbar puncture. Age-adjusted CSF-TP had a significantly lower sensitivity of only 45% in the first week (32% in the first 3 days) compared with 70% in the first week for the 0.45 g/L limit. All upper limits gained high sensitivity after the first week.ConclusionsThe low sensitivity of CSF-TP for the diagnosis of GBS is exacerbated by age-adjusted upper limits. The main role of lumbar puncture in GBS in the first week may be to help exclude other inflammatory or neoplastic etiologies of acute neuropathy. After the first week, the magnitude of the CSF-TP rise reduces the effect of different upper reference limits.

One aspect of laboratory medicine that seldom gets presented to training physicians and patients is laboratory test utilization. Effective laboratory test utilization is a strategy for performing appropriate, cost-effective diagnostic analysis without compromising quality. It can be distilled to considering what test to order, how often to order it, and on what type of patient it should be ordered on with consideration not only of diagnosis, but also resources. Test utilization does not always equate to fewer laboratory tests. While cost is often the focus as healthcare expenditures continue to rise, test utilization is also a patient safety issue. Inappropriate tests can directly result in unnecessary blood loss and may contribute towards unnecessary procedures, follow-up testing, and may even cause harm. Test utilization is also linked to patient care directly, where selection of the appropriate lab tests aid in diagnosing or monitoring a disease more accurately. This chapter outlines the importance of appropriate laboratory utilization, identifies what kinds of tests are more expensive than others and why, and the strategies that physicians and laboratories can use to ensure effective test utilization.

The final part of the laboratory testing process is known as the “Post-Analytical Phase.” In this phase, lab results are communicated to physicians. While the mechanisms of communication vary from verbal to digital, the end goal remains the same: provide accurate, timely, informative results to the physician. Although physicians are on the receiving end of this process, it may remain a bit of a black box. Common questions include: Why is this test taking so long? Why did the reference interval change since last time? Why is the lab calling me? How do I interpret a modest change in a result over time?