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Background: Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain., Methods: We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m 2 (milliliter per minute per 1.73 m 2 , as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status., Results: Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m 2 ). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology Collaboration Cr/CysC equation., Conclusions: Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs., Competing Interests: A.A. received speaker fees from AstraZeneca and holds research grants from Otsuka, all outside of the submitted work. M.M.S. received speaker fees from AstraZeneca, Otsuka, Bayer, and GlaxoSmithKline, all outside of the submitted work. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Lab testing is a high-volume activity that is often overused, leading to wasted resources and inappropriate care. Improving test ordering practices in tertiary care involves deciding where to focus scarce intervention resources, but clear guidance on how to optimize these resources is lacking. We aimed to explore context-sensitive factors and processes that inform individual decisions about laboratory stewardship interventions by speaking to key interest holders in this area., Methods: We conducted semi-structured interviews with test-ordering intervention development experts and authors of test-ordering guidance documents to explore five broad topics: 1) processes used to prioritize tests for intervention; 2) factors considered when deciding which tests to target; 3) measurement of these factors; 4) interventions selected; 5) suggestions for a framework to support these decisions. Transcripts were double coded using directed-content and thematic analysis., Results: We interviewed 14 intervention development experts. Experts noted they frequently consider test volume, test value, and patient care when deciding on a test to target. Experts indicated that quantifying many relevant factors was challenging. Processes to support these decisions often involved examining local data, obtaining buy-in, and relying on an existing guideline. Suggestions for building a framework emphasized the importance of collaboration, consideration of context and resources, and starting with "easy wins" to gain support and experience., Conclusions: Our study provides insight into the factors and processes experts consider when deciding which tests to target for intervention and can inform the development of a framework to guide the selection of tests for intervention and guideline development., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: An analytical benchmark for high-sensitivity cardiac troponin (hs-cTn) assays is to achieve a coefficient of variation (CV) of ≤ 10.0 % at the 99th percentile upper reference limit (URL) used for the diagnosis of myocardial infarction. Few prospective multicenter studies have evaluated assay imprecision and none have determined precision at the female URL which is lower than the male URL for all cardiac troponin assays., Methods: Human serum and plasma matrix samples were constructed to yield hs-cTn concentrations near the female URLs for the Abbott, Beckman, Roche, and Siemens hs-cTn assays. These materials were sent (on dry ice) to 35 Canadian hospital laboratories (n = 64 instruments evaluated) participating in a larger clinical trial, with instructions for storage, handling, and monthly testing over one year. The mean concentration, standard deviation, and CV for each instrument type and an overall pooled CV for each manufacturer were calculated., Results: The CVs for all individual instruments and overall were ≤ 10.0 % for two manufacturers (Abbott CV pooled  = 6.3 % and Beckman CV pooled  = 7.0 %). One of four Siemens Atellica instruments yielded a CV > 10.0 % (CV pooled  = 7.7 %), whereas 15 of 41 Roche instruments yielded CVs > 10.0 % at the female URL of 9 ng/L used worldwide (6 cobas e411, 1 cobas e601, 4 cobas e602, and 4 cobas e801) (CV pooled  = 11.7 %). Four Roche instruments also yielded CVs > 10.0 % near the female URL of 14 ng/L used in the United States (CV pooled  = 8.5 %)., Conclusions: The number of instruments achieving a CV ≤ 10.0 % at the female 99th-percentile URL varies by manufacturer and by instrument. Monitoring assay precision at the female URL is necessary for some assays to ensure optimal use of this threshold in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no other/known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Development of a short timeframe (6-12 months) kidney failure risk prediction model may serve to improve transitions from advanced chronic kidney disease (CKD) to kidney failure and reduce rates of unplanned dialysis. The optimal model for short timeframe kidney failure risk prediction remains unknown., Methods: This retrospective study included 1757 consecutive patients with advanced CKD (mean age 66 years, estimated glomerular filtration rate 18 mL/min/1.73 m2). We compared the performance of Cox regression models using (a) baseline variables alone, (b) time-varying variables and machine learning models, (c) random survival forest, (d) random forest classifier in the prediction of kidney failure over 6/12/24 months. Performance metrics included area under the receiver operating characteristic curve (AUC-ROC) and maximum precision at 70% recall (PrRe70). Top-performing models were applied to 2 independent external cohorts., Results: Compared to the baseline Cox model, the machine learning and time-varying Cox models demonstrated higher 6-month performance [Cox baseline: AUC-ROC 0.85 (95% CI 0.84-0.86), PrRe70 0.53 (95% CI 0.51-0.55); Cox time-varying: AUC-ROC 0.88 (95% CI 0.87-0.89), PrRe70 0.62 (95% CI 0.60-0.64); random survival forest: AUC-ROC 0.87 (95% CI 0.86-0.88), PrRe70 0.61 (95% CI 0.57-0.64); random forest classifier AUC-ROC 0.88 (95% CI 0.87-0.89), PrRe70 0.62 (95% CI 0.59-0.65)]. These trends persisted, but were less pronounced, at 12 months. The random forest classifier was the highest performing model at 6 and 12 months. At 24 months, all models performed similarly. Model performance did not significantly degrade upon external validation., Conclusions: When predicting kidney failure over short timeframes among patients with advanced CKD, machine learning incorporating time-updated data provides enhanced performance compared with traditional Cox models., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To examine local patient safety events related to the administration of anti-Rh(D) immune globin (RhIG) during pregnancy, and to follow-up with targeted educational intervention to improve knowledge of this process., Background: Administration RhIG is established treatment for the prevention of haemolytic disease of the foetus and newborn (HDFN). However, patient safety events in relation to its correct use continue to occur., Methods: A retrospective audit of patient safety events related to RhIG administration during pregnancy was performed. Targeted educational intervention in the form of PowerPoint® presentation were given to nursing staff, laboratory staff and physicians and evaluated with pre- and post-tests using multiple-choice questions given immediately before and after the presentation., Results: An annual incidence of 0.24% of patient safety events related to the administration of RhIG during pregnancy was found. These events were mostly in the preanalytical phase, for example mislabelled samples or samples for D-rosette/Kleihauer-Betke testing drawn from the baby, not the mother. Using Bayesian analysis, the probability of positive effect for the targeted educational intervention was 100% with a median improved score of 29%. This was compared with a control group using standard curriculum education intervention based on the current curriculum for nursing, laboratory and medical students which showed a median improved score of only 4.4%., Conclusions: Administration of RhIG during pregnancy is a multistep process involving health care professionals of several disciplines providing opportunities to enhance the curriculum for nursing, laboratory and medical students and to ensure on-going education., (© 2023 The Authors. Transfusion Medicine published by John Wiley & Sons Ltd on behalf of British Blood Transfusion Society.)

Background: Limitations of the Friedewald equation for low-density-lipoprotein cholesterol (F-LDLC) calculation led to the Martin-Hopkins (M-LDLC) and Sampson-National Institutes of Health (S-LDLC) equations. We studied these newer calculations of LDLC for correlation and discordance for stratification into the Canadian Cardiovascular Society (CCS) 2021 Dyslipidemia Guidelines' cardiovascular disease (CVD) risk categories., Methods: We performed analyses on lipid profiles from 3 populations: records of a hospital biochemistry laboratory (population 1), lipid clinic patients without select monogenic dyslipidemias (population 2A), and lipid clinic patients with familial hypercholesterolemia (FH; population 2B)., Results: There was very strong correlation among the 3 calculated LDLC. In populations 1 and 2A, M-LDLC and S-LDLC were progressively higher than F-LDLC as triglyceride (TG) levels increased from normal to ∼ 5 mmol/L. In population 2B, M-LDLC was higher than F-LDLC, but S-LDLC was progressively lower than F-LDLC. Using the CCS 2021 guidelines' 4 CVD risk categories, 7.0% (population 2A) to 7.2% (population 1) of cases for M-LDLC vs F-LDLC and 3.9% (population 2A) to 4.4% (population 1) of cases for S-LDLC vs F-LDLC were reclassified to an adjacent CVD risk category, mostly from a lower to a higher risk category., Conclusions: Switching from F-LDLC to S-LDLC or M-LDLC can reclassify up to ∼ 4.4% or 7.2% of patients, respectively, to another CCS CVD risk category. The difference between F-LDLC and M-LDLC or S-LDLC is greater with higher TG, and with lower LDLC. We recommend that clinical laboratories switch to reporting results from either M-LDLC or S-LDLC, but S-LDLC should not be used in FH patients, pending further studies., (Copyright © 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Plasma and RBC zinc values are unrelated in hospitalized patients. The independent association of these values with important patient outcomes is unknown., Objectives: Measure the independent association of plasma and RBC zinc with outcomes in hospitalized patients., Methods: Plasma and RBC zinc concentrations were prospectively measured within 48 h of hospitalization in consenting patients. Data were linked deterministically with population-based health administrative data to measure each association of zinc measures with 2 outcomes (time to death from any cause and likelihood of death or urgent readmission to hospital within 30-d of discharge) after adjusting for validated outcome risk scores., Results: In total, 250 people admitted to medical services were studied. Patients were ill with a 1-y baseline expected death risk (IQR) of 19.9% (6.3%-37.2%). The observed 1-y and 2-y all-cause death risks were 24.5% (95% CI: 19.6%, 30.3%) and 33.2% (95% CI: 27.3%, 39.9%), respectively. Death risk increased significantly as plasma zinc concentrations decreased ( P = 0.0001). This association persisted even after adjusting for the baseline expected death risk ( P = 0.02) with every 2-μmol/L decrease in plasma zinc concentrations being independently associated with, on average, a 35% increase in the death risk. RBC zinc concentrations were not associated with the death risk. Neither plasma nor RBC zinc concentrations were significantly associated with the 30-d death or urgent readmission rate., Conclusions: Plasma, but not RBC, zinc concentrations are independently associated with the all-cause death risk in hospitalized medical patients. Further study is required to determine whether this association is causal and identify its potential causal pathways. Curr Dev Nutr 2023;x:xx., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carl van Walraven reports financial support was provided by The Ottawa Hospital Academic Medical Association (TOHAMO)., (© 2023 The Author(s).)

Background and Objectives: Regression models incorporating laboratory tests treat unordered tests as missing and are often imputed. Imputation typically assumes that data are "missing at random" (MAR, test's order status is unrelated to its result after accounting for other variables). This study examined the validity of this assumption., Methods: We included 14 biochemistry tests. All tests were measured regardless of test order status. Test-stratified multiple linear regression determined the independent association between test result and order status after adjusting for patient age, sex, comorbidities, and patient location. Testing likelihood models were created for all tests using hospital-wide data., Results: Four hundred thirty-four patients were included (mean age [standard deviation] 60.7 [19.1], 50.5% female). In 9 of 14 tests (64.2%), test results were significantly associated with order status after adjustment. Results were significantly more abnormal when tests were ordered for 6 tests and significantly more normal for 3 tests. Test abnormality increased as testing likelihood decreased., Conclusions: These data suggest that laboratory data are often not MAR. The direction and extent of differences in missing laboratory test values varies between tests. Overall the abnormality of ordered tests increased as testing likelihood decreased. These results suggest that imputating missing laboratory data may return biased values., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Some laboratory testing practices may be of low value, leading to wasted resources and potential patient harm. Our scoping review investigated factors and processes that developers report using to inform decisions about what tests to target for practice improvement., Methods: We searched Medline on May 30th, 2019 and June 28th, 2021 and included guidelines, recommendation statements, or empirical studies related to test ordering practices. Studies were included if they were conducted in a tertiary care setting, reported making a choice about a specific test requiring intervention, and reported at least one factor informing that choice. We extracted descriptive details, tests chosen, processes used to make the choice, and factors guiding test choice., Results: From 114 eligible studies, we identified 30 factors related to test choice including clinical value, cost, prevalence of test, quality of test, and actionability of test results. We identified nine different processes used to inform decisions regarding where to spend intervention resources., Conclusions: Intervention developers face difficult choices when deciding where to put scarce resources intended to improve test utilization. Factors and processes identified here can be used to inform a framework to help intervention developers make choices relevant to improving testing practices., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Patient zinc stores are quantified with plasma or red blood cell (RBC) measures. The relationship between these 2 measures of zinc status has not been determined in a broad population of hospitalized patients., Methods: Both plasma zinc and RBC zinc were prospectively collected and measured in 252 consenting patients admitted urgently to hospital. Plasma and RBC zinc levels were measured within 48 h of admission. We collected demographic, vitals, and laboratory data for use in multivariate regression models that included markers of acute disease severity and systemic inflammation., Results: Plasma zinc and RBC zinc levels were low in 63% and 10% of hospitalized patients, respectively. Categorized zinc levels based on normal intervals for plasma and RBC zinc values were not related (χ2 0.47 [2 df] P = 0.79). The Pearson correlation coefficient between plasma zinc and RBC zinc was -0.09 (P = 0.15). After adjustments for multiple clinical covariates, the correlation coefficient remained insignificant (r = -0.11, P = 0.08). Plasma zinc was inversely associated with markers of inflammation including the neutrophil-to-lymphocyte ratio and temperature., Conclusions: Patient-specific plasma and RBC zinc are unrelated in hospitalized patients, possibly due to decreased values with acute illness seen in the former but not the latter. Future studies are required to determine which of these measures best predicts outcomes in hospitalized patients., Competing Interests: Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: The Ottawa Hospital Academic Medical Organization (TOHAMO). Expert Testimony: None declared. Patents: None declared. Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, preparation of manuscript, or final approval of manuscript., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale & Objective: Race-free estimated glomerular filtration rate (eGFR) equations incorporating creatinine with and without cystatin C were recently developed and recommended for routine use. However, the performance of these equations among kidney transplant recipients (KTRs) remains unknown., Study Design: Cross-sectional study to validate the 2021 race-free Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) eGFR equation based on creatinine alone (eGFR cr ) or based on creatinine and cystatin C (eGFR cr-cys ) among KTRs., Setting & Participants: KTRs in stable condition (N = 415) from Canada and New Zealand with same-day measurements of creatinine, cystatin C, and glomerular filtration rate (GFR) using radiolabeled diethylenetriaminepentaacetic acid., Tests Compared: The 2009 CKD-EPI eGFR cr , 2021 CKD-EPI eGFR cr , 2012 CKD-EPI eGFR cr-cys , 2021 CKD-EPI eGFR cr-cys , 2012 CKD-EPI eGFR cys , and Modification of Diet in Renal Disease (MDRD) Study eGFR equations were compared with measured GFR., Outcomes: Bias, precision, accuracy, and correct classification by CKD stage. Bias was defined as the difference between estimated and measured GFR. Precision was represented by the interquartile range. Accuracy was defined as the percentages of participants with eGFRs within 10%/20%/30% (P 10 /P 20 /P 30 ) of measured GFR, root mean square error, and mean absolute error., Results: 87% of patients studied were White, 3% Black, and 10% other races. Mean measured GFR was 53 ± 19 (SD) mL/min/1.73 m 2 . The 2009 and 2021 CKD-EPI eGFR cr equations demonstrated similar median bias (-2.3 vs -0.2 mL/min/1.73 m 2 , respectively), precision (14.5 vs 14.9 mL/min/1.73 m 2 ), and accuracy (P 10 /P 20 /P 30 , 32%/65%/84% vs 33%/63%/84%). The 2012 and 2021 CKD-EPI eGFR cr-cys equations also demonstrated similar median bias (-3.6 vs 0.3 mL/min/1.73 m 2 , respectively), precision (13.3 vs 14.3 mL/min/1.73 m 2 ), and accuracy (P 10 /P 20 /P 30 , 32%/63%/80% vs 32%/67%/83%). No clear difference in performance was detected between the 2021 CKD-EPI eGFR cr and eGFR cr-cys equations among KTRs. The proportion of correct classification by CKD stage was similar across all eGFR equations., Limitations: Moderate sample size, few patients had a GFR <30 mL/min/1.73 m 2 , and the large majority of patients were White., Conclusions: Among KTRs, the 2021 race-free CKD-EPI eGFR equations perform similarly to the previous CKD-EPI equations that included race correction terms. No significant difference in performance was observed between the 2021 CKD-EPI eGFR cr and eGFR cr-cys equations in the kidney transplant population., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Authors' disclosures of potential conflicts of interest and author contributions are found in the Appendix at the end of this article.

Background: Serial differences between intrapatient consecutive measurements can be transformed into Taylor series of variation vs time with the intersection at time = 0 (y0) equal to the total variation (analytical + biological + preanalytical). With small preanalytical variation, y0, expressed as a percentage of the mean, is equal to the variable component of the reference change value (RCV) calculation: (CVA2 + CVI2)1/2., Methods: We determined the between-day RCV of patient data for 17 analytes and compared them to healthy participants' RCVs. We analyzed 653 consecutive days of Dartmouth-Hitchcock Roche Modular general chemistry data (4.2 million results: 60% inpatient, 40% outpatient). The serial patient values of 17 analytes were transformed into 95% 2-sided RCV (RCVAlternate), and 3 sets of RCVhealthy were calculated from 3 Roche Modular analyzers' quality control summaries and CVI derived from biological variation (BV) studies using healthy participants., Results: The RCVAlternate values are similar to RCVhealthy derived from known components of variation. For sodium, chloride, bicarbonate calcium, magnesium, phosphate, alanine aminotransferase, albumin, and total protein, the RCVs are equivalent. As expected, increased variation was found for glucose, aspartate aminotransferase, creatinine, and potassium. Direct bilirubin and urea demonstrated lower variation., Conclusions: Our RCVAlternate values integrate known and unknown components of analytic, biologic, and preanalytic variation, and depict the variations observed by clinical teams that make medical decisions based on the test values. The RCVAlternate values are similar to the RCVhealthy values derived from known components of variation and suggest further studies to better understand the results being generated on actual patients tested in typical laboratory environments., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

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., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Competing interests: None declared.

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 (CV a) 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 CV a 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., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

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., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

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 <7 g/L) was 21.9 and 5.5%, respectively. High PG (≥38 g/L) had sensitivity and specificity of 76.2 and 71.5% respectively for hypergammaglobulinemia. PG ≥38 g/L had a negative predictive value (NPV) of 93.1% for monoclonal, and 96.9% for polyclonal gammopathy. A PG threshold of ≤18 g/L had of sensitivity of 0.4%, specificity of 100%, PPV of 100% and NPV of 80.1% to detect hypogammaglobulinemia (IgG <7 g/L)., 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., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

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., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest regarding this paper., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

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., (© Endocrine Society 2019.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2019 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Scurvy is a rare entity in developed countries and the diagnosis may often be delayed resulting in unnecessary investigations and/or potentially severe complications. A recent increase in the number of patients diagnosed with scurvy in our hematology clinics indicated the need to review the literature on the diagnosis and optimal management of similar patients., Methods: We conducted a retrospective chart review of patients referred to hematology at our tertiary care centre between 2010 and 2018, who were ultimately diagnosed with scurvy. Data collected from electronic medical records included baseline characteristics, clinical features on presentation, bloodwork results from initial consultation, treatment plan as well as response to treatment., Findings: Twenty-two adults patient had a diagnosis of scurvy with a mean vitamin C level of 6 μmol/L. Iron deficiency anemia (54%) and gastrointestinal disorders (54%) were the most common comorbidities noted in our cohort. Proton-pump inhibitors use was noted in 54% of patients. Bleeding (45%) and bruising (45%) were the most commonly reported clinical features. Eleven patients received oral supplementation, five had intravenous (IV) vitamin C and six were not treated. Two patients required a transition from oral to IV supplementation. Vitamin C dosing ranged between 250 and 2000 mg and the frequency varied from daily for oral therapy to every few weeks or months for IV., Interpretation: Awareness of scurvy and its associated risk factors and clinical presentation is important in the evaluation of a patient with bleeding tendency. Treatment plan should be individualized, and a careful review of patients' diet, medial history and medications is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: We set out to test the discriminative power of an age-adjusted upper reference limit for cerebrospinal fluid total protein (CSF-TP) in identifying clinically relevant causes of albuminocytological dissociation (ACD)., Methods: We reviewed the charts of 2627 patients who underwent a lumbar puncture at a tertiary care centre over a 20-year period. Samples with CSF-TP above 45 mg/dL (0.45 g/L) were included. Samples with white cell count >5×10 9 /L, red cell count >50×10 9 /L and glucose <2.5 mmol/L (45 mg/dL) were excluded as were samples with incomplete data and those taken from paediatric patients (ie, age <18 years old). Patients with CSF-TP elevated above 45 mg/dL were considered to have 'pseudo' ACD unless their CSF-TP was in excess of age-adjusted norms in which case they were considered to have 'true' ACD. Adjustment for sex was not applied to the age-adjusted norms although the importance of gender has been previously described., Results: The presence of ACD was associated with a broad range of neurological diagnoses. Among all 2627 patients with ACD, a clinical diagnosis explaining CSF-TP elevation was identified in 57% of cases. 'True' ACD was associated with a suitable diagnosis in 75% of cases, whereas patients with 'pseudo' ACD showed an appropriate diagnosis in only 51% of cases. Use of an age-adjusted upper reference limit favoured the detection of polyneuropathy patients (13.5% proportionate increase) and excluded a larger number of patients with isolated headache (10.7% proportionate decrease; p<0.0001)., Conclusions: Elevated CSF-TP is a common finding, with a range of underlying causes. Use of an age-adjusted upper reference limit for the CSF-TP value improves diagnostic specificity and helps to avoid overdiagnosis of ACD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: 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., Objective: To determine the effect of NAC on kidney function., Design: A systematic review and meta-analysis., Settings: Prospective studies, with administration of NAC, in the absence of any other change in kidney function (such as contrast administration or surgery)., Patients: 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., Measurements: Serum creatinine and/or cystatin C measurements before and after NAC administration., Methods: 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., Results: 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., Limitations: Possible heterogeneity and publication bias and lack of mechanistic data., Conclusions: 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., Systematic Review Registration: This review is registered with PROSPERO, CRD42017055984., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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&#95;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)., Competing Interests: The authors have declared that no competing interests exist.

Background: 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., Study Design: We conducted a retrospective assessment of the impact of implementing nephrology-specific M&MCs using the OM3., Setting and Participants: All physicians, residents and fellows from the division of nephrology at a large academic medical center were invited to participate., Quality Improvement Plan: Structured M&MCs were implemented to identify preventable errors and generate actions to improve quality of care and patient safety., Outcomes: Number and nature of cases reviewed, number and nature of recommendations generated through identification of preventable health system and/or cognitive factors., Measurements: 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., Results: 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: Limitations of this study include its retrospective nature and single-center design., Conclusions: 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.