Handling of hemolyzed serum samples in clinical chemistry laboratories: The Nordic hemolysis project

Under embargo until: 2020-07-09Hemolysis of blood samples is a pre-analytical challenge that often leads to sample rejection in medical laboratories [1]. Hemolysis occurs when blood cells break down and the intracellular contents leak into the surrounding fluid [2]. When hemolyzed blood samples are analyzed in medical laboratories, the content released from the blood cells can interfere with the measurement procedure, leading to erroneous results that may not reflect the patient’s clinical condition. How, and to what extent, hemolysis may affect test results depends on the analyte and the measurement method used [1]. Interference studies are performed to establish how much the various analytes, when measured by different methods, will be affected by hemolysis [3]. Based on the results, instrument-specific cut-off points are determined to prevent hemolysis from significantly affecting the clinical interpretation of laboratory results. Most instruments used in medical laboratories today can measure cell-free hemoglobin (Hb) in individual blood samples and transfer the result to the laboratory information system (LIS). These Hb results may be combined with predefined Hb cut-off points, enabling the laboratories to automatically reject or comment upon test results significantly affected by hemolysis [4]. Cut-off points for rejection of samples are commonly recommended by the manufacturers of in vitro diagnostic (IVD) analytical systems. The Clinical and Laboratory Standards Institute (CLSI) recommends that the laboratories verify the intended usefulness, strengths and limitations of manufacturer-derived cut-off points before they are implemented [5]. This is time and resource consuming for the laboratory, and may be difficult as manufacturers’ package inserts often lack information about experiment design and how the cut-off points were defined [6], [7], [8]. Consequently, many laboratories use the manufacturers’ cut-off points for hemolysis, without further verification studies [8]. The Nordic cooperation of External Quality Assurance (EQA) organizers, EQAnord, performed a large interference study in 2002 to obtain data on the effect of hemolysis on analytical performance on different clinical chemistry instruments [9]. The aims of the current study were (1) to obtain updated information about how hemolysis affects clinical chemistry test results on different instrument platforms, and (2) to obtain data on how test results from hemolyzed samples are reported in medical biochemistry hospital laboratories in the Nordic countries.publishedVersio

Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts : results from the population-based iStopMM study

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.Peer reviewe

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease : Results of the iStopMM study

Publisher Copyright: © 2022. The Author(s). © 2022. The Author(s).Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.Peer reviewe

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore present a target population for MGUS screening. This two-part study is the first study to evaluate the relationship of MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio (OR)= 1.10; 95% confidence interval (CI): 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer associated with the progression of MGUS, except for myeloid malignancies which were associated with lower risk of progression (hazard ratio (HR)=0.37; 95%CI: 0.16-0.89; p=0.028). Our findings indicate that a prior cancer are not a significant aetiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer

Handling of hemolyzed serum samples in clinical chemistry laboratories: The Nordic hemolysis project

Hemolysis of blood samples is a pre-analytical challenge that often leads to sample rejection in medical laboratories [1]. Hemolysis occurs when blood cells break down and the intracellular contents leak into the surrounding fluid [2]. When hemolyzed blood samples are analyzed in medical laboratories, the content released from the blood cells can interfere with the measurement procedure, leading to erroneous results that may not reflect the patient’s clinical condition. How, and to what extent, hemolysis may affect test results depends on the analyte and the measurement method used [1]. Interference studies are performed to establish how much the various analytes, when measured by different methods, will be affected by hemolysis [3]. Based on the results, instrument-specific cut-off points are determined to prevent hemolysis from significantly affecting the clinical interpretation of laboratory results. Most instruments used in medical laboratories today can measure cell-free hemoglobin (Hb) in individual blood samples and transfer the result to the laboratory information system (LIS). These Hb results may be combined with predefined Hb cut-off points, enabling the laboratories to automatically reject or comment upon test results significantly affected by hemolysis [4]. Cut-off points for rejection of samples are commonly recommended by the manufacturers of in vitro diagnostic (IVD) analytical systems. The Clinical and Laboratory Standards Institute (CLSI) recommends that the laboratories verify the intended usefulness, strengths and limitations of manufacturer-derived cut-off points before they are implemented [5]. This is time and resource consuming for the laboratory, and may be difficult as manufacturers’ package inserts often lack information about experiment design and how the cut-off points were defined [6], [7], [8]. Consequently, many laboratories use the manufacturers’ cut-off points for hemolysis, without further verification studies [8]. The Nordic cooperation of External Quality Assurance (EQA) organizers, EQAnord, performed a large interference study in 2002 to obtain data on the effect of hemolysis on analytical performance on different clinical chemistry instruments [9]. The aims of the current study were (1) to obtain updated information about how hemolysis affects clinical chemistry test results on different instrument platforms, and (2) to obtain data on how test results from hemolyzed samples are reported in medical biochemistry hospital laboratories in the Nordic countries

Monoclonal gammopathy of undetermined significance and COVID-19: a population-based cohort study.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadMultiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81-1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52-1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19.Black Swan Research Initiative by the International Myeloma Foundation European Research Council (ERC) European Commission Icelandic Center for Research University of Iceland Landspitali-The National University Hospital of Iceland Icelandic Cancer Societ