Publications by authors named "Aasne K Aarsand"

45 Publications

Long-term within- and between-subject biological variation of 29 routine laboratory measurands in athletes.

Clin Chem Lab Med 2021 Nov 19. Epub 2021 Nov 19.

Laboratory Medicine Department, La Paz University Hospital, Madrid, Spain.

Objectives: Within- and between-subject biological variation (BV) estimates have many applications in laboratory medicine. However, robust high-quality BV estimates are lacking for many populations, such as athletes. This study aimed to deliver BV estimates of 29 routine laboratory measurands derived from a Biological Variation Data Critical Appraisal Checklist compliant design in a population of high-endurance athletes.

Methods: Eleven samples per subject were drawn from 30 triathletes monthly, during a whole sport season. Serum samples were measured in duplicate for proteins, liver enzymes, lipids and kidney-related measurands on an Advia2400 (Siemens Healthineers). After outlier and homogeneity analysis, within-subject (CV) and between-subject (CV) biological variation estimates were delivered (CV-ANOVA and log-ANOVA, respectively) and a linear mixed model was applied to analyze the effect of exercise and health related variables.

Results: Most CV estimates were similar or only slightly higher in athletes compared to those reported for the general population, whereas two- to three-fold increases were observed for amylase, ALT, AST and ALP. No effect of exercise and health related variables were observed on the CV estimates. For seven measurands, data were not homogeneously distributed and BV estimates were therefore not reported.

Conclusions: The observation of higher CV estimates in athletes than what has been reported for the general population may be related to physiological stress over time caused by the continuous practice of exercise. The BV estimates derived from this study could be applied to athlete populations from disciplines in which they exercise under similar conditions of intensity and duration.
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http://dx.doi.org/10.1515/cclm-2021-0910DOI Listing
November 2021

Biological variation estimates of thyroid related measurands - meta-analysis of BIVAC compliant studies.

Clin Chem Lab Med 2021 Nov 15. Epub 2021 Nov 15.

Analytical Quality Commission, Spanish Society of Laboratory Medicine (SEQCML), Barcelona, Spain.

Objectives: Testing for thyroid disease constitutes a high proportion of the workloads of clinical laboratories worldwide. The setting of analytical performance specifications (APS) for testing methods and aiding clinical interpretation of test results requires biological variation (BV) data. A critical review of published BV studies of thyroid disease related measurands has therefore been undertaken and meta-analysis applied to deliver robust BV estimates.

Methods: A systematic literature search was conducted for BV studies of thyroid related analytes. BV data from studies compliant with the Biological Variation Data Critical Appraisal Checklist (BIVAC) were subjected to meta-analysis. Global estimates of within subject variation (CV) enabled determination of APS (imprecision and bias), indices of individuality, and indicative estimates of reference change values.

Results: The systematic review identified 17 relevant BV studies. Only one study (EuBIVAS) achieved a BIVAC grade of A. Methodological and statistical issues were the reason for B and C scores. The meta-analysis derived CV generally delivered lower APS for imprecision than the mean CV of the studies included in this systematic review.

Conclusions: Systematic review and meta-analysis of studies of BV of thyroid disease biomarkers have enabled delivery of well characterized estimates of BV for some, but not all measurands. The newly derived APS for imprecision for both free thyroxine and triiodothyronine may be considered challenging. The high degree of individuality identified for thyroid related measurands reinforces the importance of RCVs. Generation of BV data applicable to multiple scenarios may require definition using "big data" instead of the demanding experimental approach.
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http://dx.doi.org/10.1515/cclm-2021-0904DOI Listing
November 2021

Biological variation of venous acid-base status measurands in athletes.

Clin Chim Acta 2021 Nov 5;523:497-503. Epub 2021 Nov 5.

Laboratory Medicine Department, La Paz University Hospital, Madrid, Spain.

Background: Analysis of acid-base status (ABS) is requested in a wide range of clinical scenarios, including in the assessment of athletes' performance and follow up, but there is a lack of high-quality biological variation (BV) data. The aims of this study were to estimate the BV of ABS related parameters in athletes and to evaluate if variables related to exercise may influence the estimates.

Material And Methods: Eleven samples from 30 triathletes were drawn, on a monthly basis. The samples were measured for pH, pCO, bicarbonate, base excess, TCO, Ca and lactate. A CV-ANOVA was performed to calculate within-subject (CV) estimates and a linear mixed model was applied to analyze the effect of the folowing variables on the BV; health status, sampling interval, intensity and duration of the exercise.

Results: For all ABS parameters except for lactate, higher CV estimates were found in athletes than what have been reported for the general population. No significant effect of the exercise and sampling related variables were observed, except for Ca.

Conclusion: This difference founds in ABS parameters between athletes and the general population could be explained by the physiological stress during exercise. Laboratories attending this population could use these BV estimates to establish quality goals.
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http://dx.doi.org/10.1016/j.cca.2021.11.001DOI Listing
November 2021

Personalized reference intervals: Using estimates of within-subject or within-person biological variation requires different statistical approaches.

Clin Chim Acta 2021 Oct 28. Epub 2021 Oct 28.

Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Haraldsplass Deaconess Hospital, Bergen, Norway; Norwegian Porphyria Centre and Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway.

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http://dx.doi.org/10.1016/j.cca.2021.10.034DOI Listing
October 2021

Within- and between-subject biological variation data for serum zinc, copper and selenium obtained from 68 apparently healthy Turkish subjects.

Clin Chem Lab Med 2021 Oct 22. Epub 2021 Oct 22.

Acibadem Labmed Clinical Laboratories, Atasehir, Istanbul, Turkey.

Objectives: Trace elements (TrEL) are nutritionally essential components in maintaining health and preventing diseases. There is a lack of reliable biological variation (BV) data for TrELs, required for the diagnosis and monitoring of TrEL disturbances. In this study, we aimed to provide updated within- and between-subject BV estimates for zinc (Zn), copper (Cu) and selenium (Se).

Methods: Weekly serum samples were drawn from 68 healthy subjects (36 females and 32 males) for 10 weeks and stored at -80 °C prior to analysis. Serum Zn, Cu and Se levels were measured using inductively-coupled plasma mass spectrometry (ICP-MS). Outlier and variance homogeneity analyses were performed followed by CV-ANOVA (Røraas method) to determine BV and analytical variation estimates with 95% CI and the associated reference change values (RCV) for all subjects, males and females.

Results: Significant differences in mean concentrations between males and females were observed, with absolute and relative (%) differences for Zn at 0.5 μmol/L (3.5%), Cu 2.0 μmol/L (14.1%) and Se 0.06 μmol/L (6.0%). The within-subject BV (CV [95% CI]) estimates were 8.8% (8.2-9.3), 7.8% (7.3-8.3) and 7.7% (7.2-8.2) for Zn, Cu and Se, respectively. Within-subject biological variation (CV) estimates derived for male and female subgroups were similar for all three TrELs. Marked individuality was observed for Cu and Se.

Conclusions: The data of this study provides updated BV estimates for serum Zn, Cu and Se derived from a stringent protocol and state of the art methodologies. Furthermore, Cu and Se display marked individuality, highlighting that population based reference limits should not be used in the monitoring of patients.
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http://dx.doi.org/10.1515/cclm-2021-0886DOI Listing
October 2021

The European Biological Variation Study (EuBIVAS): Biological Variation Data for Coagulation Markers Estimated by a Bayesian Model.

Clin Chem 2021 Sep;67(9):1259-1270

Laboratory Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: For biological variation (BV) data to be safely used, data must be reliable and relevant to the population in which they are applied. We used samples from the European Biological Variation Study (EuBIVAS) to determine BV of coagulation markers by a Bayesian model robust to extreme observations and used the derived within-participant BV estimates [CVP(i)] to assess the applicability of the BV estimates in clinical practice.

Method: Plasma samples were drawn from 92 healthy individuals for 10 consecutive weeks at 6 European laboratories and analyzed in duplicate for activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen, D-dimer, antithrombin (AT), protein C, protein S free, and factor VIII (FVIII). A Bayesian model with Student t likelihoods for samples and replicates was applied to derive CVP(i) and predicted BV estimates with 95% credibility intervals.

Results: For all markers except D-dimer, CVP(i) were homogeneously distributed in the overall study population or in subgroups. Mean within-subject estimates (CVI) were <5% for APTT, PT, AT, and protein S free, <10% for protein C and FVIII, and <12% for fibrinogen. For APTT, protein C, and protein S free, estimates were significantly lower in men than in women ≤50 years.

Conclusion: For most coagulation markers, a common CVI estimate for men and women is applicable, whereas for APTT, protein C, and protein S free, sex-specific reference change values should be applied. The use of a Bayesian model to deliver individual CVP(i) allows for improved interpretation and application of the data.
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http://dx.doi.org/10.1093/clinchem/hvab100DOI Listing
September 2021

The European Biological Variation Study (EuBIVAS): a summary report.

Clin Chem Lab Med 2021 May 31. Epub 2021 May 31.

Central Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Biological variation (BV) data have many important applications in laboratory medicine. Concerns about quality of published BV data led the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) 1st Strategic Conference to indicate need for new studies to generate BV estimates of required quality. In response, the EFLM Working Group on BV delivered the multicenter European Biological Variation Study (EuBIVAS). This review summarises the EuBIVAS and its outcomes. Serum/plasma samples were taken from 91 ostensibly healthy individuals for 10 consecutive weeks at 6 European centres. Analysis was performed by Siemens ADVIA 2400 (clinical chemistry), Cobas Roche 8000, c702 and e801 (proteins and tumor markers/hormones respectively), ACL Top 750 (coagulation parameters), and IDS iSYS or DiaSorin Liaison (bone biomarkers). A strict preanalytical and analytical protocol was applied. To determine BV estimates with 95% CI, CV-ANOVA after analysis of outliers, homogeneity and trend analysis or a Bayesian model was applied. EuBIVAS has so far delivered BV estimates for 80 different measurands. Estimates for 10 measurands (Non-HDL Cholesterol, S100-β protein, neuron-specific enolase, soluble transferrin receptor, intact fibroblast growth-factor-23, uncarboxylated-unphosphorylated matrix-Gla protein, human epididymis protein-4, free, conjugated and %free prostate-specific antigen), prior to EuBIVAS, have not been available. BV data for creatinine and troponin I were obtained using two analytical methods in each case. The EuBIVAS has delivered high-quality BV data for a wide range of measurands. The BV estimates are for many measurands lower than those previously reported, having an impact on the derived analytical performance specifications and reference change values.
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http://dx.doi.org/10.1515/cclm-2021-0370DOI Listing
May 2021

Current Utility and Reliability of Biological Variability.

Clin Chem 2021 Aug;67(8):1050-1055

Sr. Scientific Affairs Manager, Roche Diagnostics Corporation, Indianapolis, IN, USA.

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http://dx.doi.org/10.1093/clinchem/hvab055DOI Listing
August 2021

Within- and between-subject biological variation data for tumor markers based on the European Biological Variation Study.

Clin Chem Lab Med 2021 May 10. Epub 2021 May 10.

EFLM Working Group on Biological Variation, Milan, Italy.

Objectives: Reliable biological variation (BV) data are required for the clinical use of tumor markers in the diagnosis and monitoring of treatment effects in cancer. The European Biological Variation Study (EuBIVAS) was established by the EFLM Biological Variation Working Group to deliver BV data for clinically important measurands. In this study, EuBIVAS-based BV estimates are provided for cancer antigen (CA) 125, CA 15-3, CA 19-9, carcinoembryonic antigen, cytokeratin-19 fragment, alpha-fetoprotein and human epididymis protein 4.

Methods: Subjects from five European countries were enrolled in the study, and weekly samples were collected from 91 healthy individuals (53 females and 38 males; 21-69 years old) for 10 consecutive weeks. All samples were analyzed in duplicate within a single run. After excluding outliers and homogeneity analysis, the BVs of tumor markers were determined by CV-ANOVA on trend-corrected data, when relevant (Røraas method).

Results: Marked individuality was found for all tumor markers. CYFRA 21-1 was the measurand with the highest index of individuality (II) at 0.67, whereas CA 19-9 had the lowest II at 0.07. The CV s of HE4, CYFRA 21-1, CA 19-9, CA 125 and CA 15-3 of pre- and postmenopausal females were significantly different from each other.

Conclusions: This study provides updated BV estimates for several tumor markers, and the findings indicate that marked individuality is characteristic. The use of reference change values should be considered when monitoring treatment of patients by means of tumor markers.
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http://dx.doi.org/10.1515/cclm-2021-0283DOI Listing
May 2021

Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran.

J Inherit Metab Dis 2021 07 4;44(4):961-971. Epub 2021 May 4.

Norwegian Porphyria Centre (NAPOS), Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway.

Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 μmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 μmol/L; range: 10-129 vs median tHcy: 14.5 μmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5'-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 μmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 μmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-β-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria.
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http://dx.doi.org/10.1002/jimd.12391DOI Listing
July 2021

European Biological Variation Study (EuBIVAS): within- and between-subject biological variation estimates for serum thyroid biomarkers based on weekly samplings from 91 healthy participants.

Clin Chem Lab Med 2021 Feb 9. Epub 2021 Feb 9.

Laboratory Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objectives: Thyroid biomarkers are fundamental for the diagnosis of thyroid disorders and for the monitoring and treatment of patients with these diseases. The knowledge of biological variation (BV) is important to define analytical performance specifications (APS) and reference change values (RCV). The aim of this study was to deliver BV estimates for thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), thyroglobulin (TG), and calcitonin (CT).

Methods: Analyses were performed on serum samples obtained from the European Biological Variation Study population (91 healthy individuals from six European laboratories; 21-69 years) on the Roche Cobas e801 at the San Raffaele Hospital (Milan, Italy). All samples from each individual were evaluated in duplicate within a single run. The BV estimates with 95% CIs were obtained by CV-ANOVA, after analysis of variance homogeneity and outliers.

Results: The within-subject (CV ) BV estimates were for TSH 17.7%, FT3 5.0%, FT4 4.8%, TG 10.3, and CT 13.0%, all significantly lower than those reported in the literature. No significant differences were observed for BV estimates between men and women.

Conclusions: The availability of updated, in the case of CT not previously published, BV estimates for thyroid markers based on the large scale EuBIVAS study allows for refined APS and associated RCV applicable in the diagnosis and management of thyroid and related diseases.
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http://dx.doi.org/10.1515/cclm-2020-1885DOI Listing
February 2021

Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators.

Int J Mol Sci 2021 Jan 12;22(2). Epub 2021 Jan 12.

Department of Biomedicine, University of Bergen, 5020 Bergen, Norway.

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase () gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP.
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http://dx.doi.org/10.3390/ijms22020675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827610PMC
January 2021

Biological Variation of Cardiac Troponins in Health and Disease: A Systematic Review and Meta-analysis.

Clin Chem 2021 01;67(1):256-264

Norwegian Porphyria Centre, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway.

Background: Many studies have assessed the biological variation (BV) of cardiac-specific troponins (cTn), reporting widely varying within-subject BV (CVI) estimates. The aim of this study was to provide meta-analysis-derived BV estimates for troponin I (cTnI) and troponin T (cTnT) for different sampling intervals and states of health.

Methods: Relevant studies were identified by a systematic literature search. Studies were classified according to their methodological quality by the Biological Variation Data Critical Appraisal Checklist (BIVAC). Meta-analyses of BIVAC-compliant studies were performed after stratification by cTn isoform, exclusion of results below the limit of detection, states of health, and sampling interval to deliver reference change values (RCV), index of individuality (II) and analytical performance specifications (APS) for these settings.

Results: Sixteen and 15 studies were identified for cTnI and cTnT, respectively, out of which 6 received a BIVAC grade A. Five studies had applied contemporary cTnI assays, but none contemporary cTnT. High-sensitivity (hs-) cTnI and cTnT delivered similar estimates in all settings. Long-term CVI estimates (15.1; 11.3%) derived from healthy individuals were higher than short-term (4.3%; 5.3%) for hs-cTnI and hs-cTnT, respectively, although confidence intervals overlapped. Estimates derived from diseased subjects were similar to estimates in healthy individuals for all settings.

Conclusions: This study provides robust estimates for hs-cTnI and hs-cTnT applicable for different clinical settings and states of health, allowing for the use of RCV both to aid in the diagnosis of myocardial injury and for prognosis. BV-based APS appear too strict for some currently available technologies.
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http://dx.doi.org/10.1093/clinchem/hvaa261DOI Listing
January 2021

Personalized Reference Intervals in Laboratory Medicine: A New Model Based on Within-Subject Biological Variation.

Clin Chem 2021 01;67(2):374-384

Department of Medical Biochemistry and Pharmacology, Norwegian Porphyria Centre, Haukeland University Hospital, Bergen, Norway.

Background: The concept of personalized medicine has received widespread attention in the last decade. However, personalized medicine depends on correct diagnosis and monitoring of patients, for which personalized reference intervals for laboratory tests may be beneficial. In this study, we propose a simple model to generate personalized reference intervals based on historical, previously analyzed results, and data on analytical and within-subject biological variation.

Methods: A model using estimates of analytical and within-subject biological variation and previous test results was developed. We modeled the effect of adding an increasing number of measurement results on the estimation of the personal reference interval. We then used laboratory test results from 784 adult patients (>18 years) considered to be in a steady-state condition to calculate personalized reference intervals for 27 commonly requested clinical chemistry and hematology measurands.

Results: Increasing the number of measurements had little impact on the total variation around the true homeostatic set point and using ≥3 previous measurement results delivered robust personalized reference intervals. The personalized reference intervals of the study participants were different from one another and, as expected, located within the common reference interval. However, in general they made up only a small proportion of the population-based reference interval.

Conclusions: Our study shows that, if using results from patients in steady state, only a few previous test results and reliable estimates of within-subject biological variation are required to calculate personalized reference intervals. This may be highly valuable for diagnosing patients as well as for follow-up and treatment.
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http://dx.doi.org/10.1093/clinchem/hvaa233DOI Listing
January 2021

Critical appraisal and meta-analysis of biological variation estimates for kidney related analytes.

Clin Chem Lab Med 2020 Oct 3. Epub 2020 Oct 3.

Norwegian Organization for Quality Improvement of Laboratory Examinations (NOKLUS), Haraldsplass Deaconess Hospital, Bergen, Norway.

Objective: Kidney markers are some of the most frequently used laboratory tests in patient care, and correct clinical decision making depends upon knowledge and correct application of biological variation (BV) data. The aim of this study was to review available BV data and to provide updated BV estimates for the following kidney markers in serum and plasma; albumin, creatinine, cystatin C, chloride, potassium, sodium and urea.

Content: Relevant studies were identified from a historical BV database as well as by systematic literature searches. Retrieved publications were appraised by the Biological Variation Data Critical Appraisal Checklist (BIVAC). Meta-analyses of BIVAC compliant studies with similar design were performed to deliver global estimates of within-subject (CVI) and between-subject (CVG) BV estimates. Out of the 61 identified papers, three received a BIVAC grade A, four grade B, 48 grade C, five grade D grade and one was not appraised as it did not report numerical BV estimates. Most studies were identified for creatinine (n=48). BV estimates derived from the meta-analysis were in general lower than previously reported estimates for all analytes except urea. For some measurands, BV estimates may be influenced by age or states of health, but further data are required.

Summary: This review provides updated global BV estimates for kidney related measurands. For all measurands except for urea, these estimates were lower than previously reported.

Outlook: For the measurands analyzed in this review, there are sufficient well-designed studies available to publish a trustworthy estimate of BV. However, for a number of newly appearing kidney markers no suitable data is available and additional studies are required.
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http://dx.doi.org/10.1515/cclm-2020-1168DOI Listing
October 2020

European Biological Variation Study (EuBIVAS): within- and between-subject biological variation estimates for serum biointact parathyroid hormone based on weekly samplings from 91 healthy participants.

Ann Transl Med 2020 Jul;8(14):855

Laboratory Medicine, Ospedale San Raffaele, Milan, Italy.

Background: The European Biological Variation Study (EuBIVAS) was created by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group on Biological Variation to establish high-quality biological variation (BV) estimates for clinically important measurands. In this study, the aim was to deliver reliable BV estimates for the biointact parathyroid hormone (PTH 1-84).

Methods: Serum samples were obtained from a population of 91 healthy individuals (38 men, 43 pre-menopausal women, and 10 post-menopausal women; 21-69 years) from 5 European countries, with all samples stored at -80 °C prior to analysis. PTH 1-84 analysis was performed at the San Raffaele Hospital (Milan, Italy) on the Roche Cobas e801. All samples from each individual were analysed in duplicate within a single run. CV-ANOVA was applied, after analysis of variance homogeneity and outliers, to obtain BV estimates for PTH 1-84 with 95% CIs.

Results: The within-subject BV [CV (95% CI)] estimates were significantly different between men and women [13.0% (12.1-14.2%) and 15.2% (14.3-16.3%), respectively], while the between-subject estimates [CV (95% CI)] were similar (men: 26.8% (21.4-35.1%), pre-menopausal women: 27.8% (22.7-36.1%)], allowing for delivery of updated analytical performance specifications and reference change values.

Conclusions: Updated BV estimates for serum PTH 1-84 based on the large-scale EuBIVAS may be beneficial for the diagnosis and management of parathyroid glands and bone turnover pathologies.
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http://dx.doi.org/10.21037/atm-19-4498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396758PMC
July 2020

Biological variation of morning serum cortisol: Updated estimates from the European biological variation study (EuBIVAS) and meta-analysis.

Clin Chim Acta 2020 10 25;509:268-272. Epub 2020 Jun 25.

Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Norway.

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http://dx.doi.org/10.1016/j.cca.2020.06.038DOI Listing
October 2020

Analytical Performance Specifications for Lipoprotein(a), Apolipoprotein B-100, and Apolipoprotein A-I Using the Biological Variation Model in the EuBIVAS Population.

Clin Chem 2020 05;66(5):727-736

Laboratory Medicine, Ospedale San Raffaele, Milan, Italy.

Background: With increased interest in lipoprotein(a) (Lp[a]) concentration as a target for risk reduction and growing clinical evidence of its impact on cardiovascular disease (CVD) risk, rigorous analytical performance specifications (APS) and accuracy targets for Lp(a) are required. We investigated the biological variation (BV) of Lp(a), and 2 other major biomarkers of CVD, apolipoprotein A-I (apoA-I) and apolipoprotein B-100 (apoB), in the European Biological Variation Study population.

Method: Serum samples were drawn from 91 healthy individuals for 10 consecutive weeks at 6 European laboratories and analyzed in duplicate on a Roche Cobas 8000 c702. Outlier, homogeneity, and trend analysis were performed, followed by CV-ANOVA to determine BV estimates and their 95% CIs. These estimates were used to calculate APS and reference change values. For Lp(a), BV estimates were determined on normalized concentration quintiles.

Results: Within-subject BV estimates were significantly different between sexes for Lp(a) and between women aged <50 and >50 years for apoA-I and apoB. Lp(a) APS was constant across concentration quintiles and, overall, lower than APS based on currently published data, whereas results were similar for apoA-I and apoB.

Conclusion: Using a fully Biological Variation Data Critical Appraisal Checklist (BIVAC)-compliant protocol, our study data confirm BV estimates of Lp(a) listed in the European Federation of Clinical Chemistry and Laboratory Medicine database and reinforce concerns expressed in recent articles regarding the suitability of older APS recommendations for Lp(a) measurements. Given the heterogeneity of Lp(a), more BIVAC-compliant studies on large numbers of individuals of different ethnic groups would be desirable.
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http://dx.doi.org/10.1093/clinchem/hvaa054DOI Listing
May 2020

The European Biological Variation Study (EuBIVAS): weekly biological variation of cardiac troponin I estimated by the use of two different high-sensitivity cardiac troponin I assays.

Clin Chem Lab Med 2020 09;58(10):1741-1747

Servizio Medicina di Laboratorio, Ospedale San Raffaele, Milan, Italy.

Background Cardiac troponins (cTn) are specific markers for cardiac damage and acute coronary syndromes. The availability of new high-sensitivity assays allows cTn detection in healthy people, thus permitting the estimation of biological variation (BV) of cTn. The knowledge of BV is important to define analytical performance specifications (APS) and reference change values (RCVs). The aim of this study was to estimate the within- and between-subject weekly BV (CVI, CVG) of cTnI applying two high-sensitivity cTnI assays, using European Biological Variation Study (EuBIVAS) specimens. Methods Thirty-eight men and 53 women underwent weekly fasting blood drawings for 10 consecutive weeks. Duplicate measurements were performed with Singulex Clarity (Singulex, USA) and Siemens Atellica (Siemens Healthineers, Germany). Results cTnI was measurable in 99.4% and 74.3% of the samples with Singulex and Atellica assays, respectively. Concentrations were significantly higher in men than in women with both methods. The CVI estimates with 95% confidence interval (CI) were for Singulex 16.6% (15.6-17.7) and for Atellica 13.8% (12.7-15.0), with the observed difference likely being caused by the different number of measurable samples. No significant CVI differences were observed between men and women. The CVG estimates for women were 40.3% and 36.3%, and for men 65.3% and 36.5% for Singulex and Atellica, respectively. The resulting APS and RCVs were similar for the two methods. Conclusions This is the first study able to estimate cTnI BV for such a large cohort of well-characterized healthy individuals deriving objective APS and RCV values for detecting significant variations in cTnI serial measurements, even within the 99th percentile.
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http://dx.doi.org/10.1515/cclm-2019-1182DOI Listing
September 2020

Health-related quality of life in porphyria cutanea tarda: a cross-sectional registry based study.

Health Qual Life Outcomes 2020 Mar 30;18(1):84. Epub 2020 Mar 30.

Department of Medical Biochemistry and Pharmacology, Norwegian Porphyria Centre (NAPOS), Haukeland University Hospital, N-5021, Bergen, Norway.

Background: Porphyria cutanea tarda (PCT) is a rare, photosensitive disease characterized by skin fragility and blistering on sun-exposed areas. There is little previous research on how this condition affects health-related quality of life (HRQoL) and to the best of our knowledge this is the largest sample of PCT patients surveyed about their HRQoL. The aims of this study were to describe HRQoL, symptoms, susceptibility factors, disease activity and treatment in patients with PCT, and investigate the associations between these factors.

Methods: This is a cross-sectional, retrospective study based on patient-reported outcome and laboratory data. The Norwegian Porphyria Centre diagnoses all patients with PCT in Norway, all of whom are invited to participate in the Norwegian Porphyria Registry. Between December 2013-2015, 111 patients received a postal questionnaire and invitation to participate.

Results: Sixty-eight persons responded, with seven being excluded due to prolonged response time or missing information, resulting in 61 participants in the final analyses (55%). Median age was 60 years and 33 were female. We found a moderate negative relationship between the type and localisation of PCT symptoms and both mental (r = -.354 p < 0.01) and physical (r = -.441, p < 0.01) aspects of HRQoL. Participants who had started treatment when answering the questionnaire reported significantly better physical functioning and less bodily pain than those who had not started treatment. We did not observe an association between biochemical markers of disease activity and symptoms or HRQoL. Itching, a symptom that has received little attention in PCT was reported by 59% of the participants.

Conclusions: Our results show that reduced HRQoL is associated with more symptoms and not having started treatment. PCT is a rare disease, and there is a need for the development of best-practice guidelines to facilitate good patient care.
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http://dx.doi.org/10.1186/s12955-020-01328-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106654PMC
March 2020

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

Hepatology 2020 05 7;71(5):1546-1558. Epub 2019 Nov 7.

Alnylam Pharmaceuticals, Cambridge, MA.

Background And Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.

Approach And Results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization.

Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.
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http://dx.doi.org/10.1002/hep.30936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255459PMC
May 2020

Systematic review and meta-analysis of within-subject and between-subject biological variation estimates of 20 haematological parameters.

Clin Chem Lab Med 2019 Dec;58(1):25-32

Department of Medical Biochemistry and Pharmacology, Norwegian Porphyria Centre (NAPOS), Haukeland University Hospital, Bergen, Norway.

Background Interpretation of the complete blood count (CBC) parameters requires reliable biological variation (BV) data. The aims of this study were to appraise the quality of publications reporting BV data for CBC parameters by applying the BV Data Critical Appraisal Checklist (BIVAC) and to deliver global BV estimates based on BIVAC compliant studies. Methods Relevant publications were identified by a systematic literature search and evaluated for their compliance with the 14 BIVAC criteria, scored as A, B, C or D, indicating decreasing compliance. Global CVI and CVG estimates with 95% CI were delivered by a meta-analysis approach using data from BIVAC compliant papers (grades A-C). Results In total, 32 studies were identified; four received a BIVAC grade A, 2 B, 20 C and 6 D. Meta-analysis derived CVI and CVG estimates were generally lower or in line with those published in a historical BV database available online. Except for reticulocytes, CVI estimates of erythrocyte related parameters were below 3%, whereas platelet (except MPV and PDW) and leukocyte related parameters ranged from 5% to 15%. Conclusions A systematic review of CBC parameters has provided updated, global estimates of CVI and CVG that will be included in the newly published European Federation of Clinical Chemistry and Laboratory Medicine BV Database.
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http://dx.doi.org/10.1515/cclm-2019-0658DOI Listing
December 2019

Self-efficacy and self-management strategies in acute intermittent porphyria.

BMC Health Serv Res 2019 Jul 3;19(1):444. Epub 2019 Jul 3.

Norwegian Porphyria Centre (NAPOS), Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Post Office Box 1400, N-5021, Bergen, Norway.

Background: Acute intermittent porphyria (AIP) is an inherited metabolic disease with low clinical penetrance caused by mutations in the hydroxymethylbilane (HMBS) gene. Although most patients experience little or no symptoms, serious attacks may include excruciating pain, severe electrolyte disturbances, paresis, and respiratory failure. Several drugs and lifestyle factors are potential attack inducers and avoiding known triggers is important to avoid symptomatic disease in both patients and genetically predisposed carriers. Our aim in this study was to describe self-efficacy and self-management strategies in self-reported symptomatic and asymptomatic HMBS mutation carriers, and to elucidate motives for predictive genetic testing.

Methods: This is a cross-sectional retrospective survey with postal questionnaires. We received responses from 140 HMBS carriers for the general self-efficacy scale (GSES), study-specific questions about symptoms, self-management strategies and motives for genetic testing and satisfaction with the genetic counseling scale (SCS).

Results: The results indicated high levels of self-efficacy in these Norwegian HMBS mutation carriers. Both self-reported symptomatic and asymptomatic cases recorded changes in behavior after diagnosis, such as avoiding possible triggering drugs and aspiring recommended eating habits. They were in general satisfied with the genetic counseling they had received. The possibility to prevent disease and learn about the risk of their children was their most important motives to undergo genetic testing.

Conclusions: This study indicates that continuing to provide information, counseling and education is beneficial in AIP, and that HMBS mutation carriers, both those self-assessed as asymptomatic and as symptomatic, are using their knowledge to avoid triggering factors.
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http://dx.doi.org/10.1186/s12913-019-4285-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607542PMC
July 2019

A Bayesian Approach to Biological Variation Analysis.

Clin Chem 2019 08 1;65(8):995-1005. Epub 2019 Jul 1.

Department of Mathematics, University of Bergen, Norway.

Background: Biological variation (BV) data have many applications for diagnosing and monitoring disease. The standard statistical approaches for estimating BV are sensitive to "noisy data" and assume homogeneity of within-participant CV. Prior knowledge about BV is mostly ignored. The aims of this study were to develop Bayesian models to calculate BV that () are robust to "noisy data," () allow heterogeneity in the within-participant CVs, and () take advantage of prior knowledge.

Method: We explored Bayesian models with different degrees of robustness using adaptive Student distributions instead of the normal distributions and when the possibility of heterogeneity of the within-participant CV was allowed. Results were compared to more standard approaches using chloride and triglyceride data from the European Biological Variation Study.

Results: Using the most robust Bayesian approach on a raw data set gave results comparable to a standard approach with outlier assessments and removal. The posterior distribution of the fitted model gives access to credible intervals for all parameters that can be used to assess reliability. Reliable and relevant priors proved valuable for prediction.

Conclusions: The recommended Bayesian approach gives a clear picture of the degree of heterogeneity, and the ability to crudely estimate personal within-participant CVs can be used to explore relevant subgroups. Because BV experiments are expensive and time-consuming, prior knowledge and estimates should be considered of high value and applied accordingly. By including reliable prior knowledge, precise estimates are possible even with small data sets.
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http://dx.doi.org/10.1373/clinchem.2018.300145DOI Listing
August 2019

European Biological Variation Study (EuBIVAS): Within- and Between-Subject Biological Variation Data for 15 Frequently Measured Proteins.

Clin Chem 2019 08 6;65(8):1031-1041. Epub 2019 Jun 6.

Clinical Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Background: The European Biological Variation Study (EuBIVAS) was established to deliver rigorously determined data for biological variation (BV). Here, EuBIVAS-based BV estimates are provided for α-acid glycoprotein, α-antitrypsin, albumin, β-microglobulin, ceruloplasmin, complement component 3, complement component 4, C-reactive protein (CRP), cystatin C, haptoglobin, IgA, IgG, IgM, soluble transferrin receptor (sTfR), and transferrin (Trf), together with their associated analytical performance specifications (APSs) and reference change values (RCVs).

Method: Serum samples from weekly blood samplings of 91 healthy study participants (38 males and 53 females, ages 21-69 years old) over 10 consecutive weeks in 6 European laboratories were stored at -80 °C before duplicate analysis on a Roche Cobas c702. Outlier and variance homogeneity analyses were performed followed by CV-ANOVA on trend-corrected data if relevant, to determine BV and analytical variation estimates with CI and the associated RCV.

Results: For the acute phase proteins, several participants experienced mild inflammatory episodes during the study, requiring exclusion of 7% of the 25290 results. Within-subject BV (CV) estimates for specific proteins obtained in our study were lower than those available in the online 2014 BV database, except for Trf, whereas between-subject BV (CV) estimates were similar. CV and CV estimates for sTfR, which have not previously been published, were 6.0% and 19.1%, respectively.

Conclusions: In addition to new BV estimates for sTfR, this EuBIVAS substudy generated more demanding APS for frequently requested plasma specific proteins. APS for CRP should not be calculated from BV data except when CRP is used as a risk factor for cardiovascular disease.
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http://dx.doi.org/10.1373/clinchem.2019.304618DOI Listing
August 2019

Biological variation data for lipid cardiovascular risk assessment biomarkers. A systematic review applying the biological variation data critical appraisal checklist (BIVAC).

Clin Chim Acta 2019 Aug 16;495:467-475. Epub 2019 May 16.

Norwegian Porphyria Centre, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; Department of Global Health and Primary Care, Faculty of Medicine, University of Bergen, Norway; Norwegian Organization for Quality Improvement of Laboratory Examinations, Noklus, Haraldsplass Deaconess Hospital, Bergen, Norway.

Background: Biological variation (BV) data can be used to set analytical performance specifications (APS) for lipid assays. Poor performance will impact upon the efficacy of international guidelines for cardiovascular risk assessment (CVR) and relevant clinical decision limits. This systematic review applies the Biological Variation Data Critical Appraisal Checklist (BIVAC) to published studies of BV of CVR biomarkers enabling metanalysis of the data.

Methods: Studies of BV of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and apolipoproteins A and B, retrieved using a systematic literature search, were evaluated and graded using the BIVAC. Meta-analysis of CV and CV estimates were performed utilizing weightings based upon BIVAC grades and the width of the data confidence intervals.

Results: Applying the BIVAC, ten publications were graded as D, 43 as C, 5 as B and 1 as A (fully compliant). A total of 196 CV and 87 CV estimates were available for the different lipid measurands. The meta-analysis-derived BV data estimates were generally concordant with those in the online 2014 BV database.

Conclusions: Application of BIVAC identifies BV data suitable for many important applications including setting APS. Additionally, this review identifies a need for new BIVAC compliant studies to deliver BV reference data in different subpopulations.
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http://dx.doi.org/10.1016/j.cca.2019.05.013DOI Listing
August 2019

International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias.

Genet Med 2019 11 10;21(11):2605-2613. Epub 2019 May 10.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs with biochemically and clinically verified information. Therefore, an international collaborative with the European Porphyria Network and the National Institutes of Health/National Center for Advancing Translational Sciences/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NCATS/NIDDK)-sponsored Porphyrias Consortium of porphyria diagnostic experts is establishing an online database that will collate biochemical and clinical evidence verifying the pathogenicity of the published and newly identified variants in the AHP-causing genes. The overall goal of the International Porphyria Molecular Diagnostic Collaborative is to determine the pathogenic and benign variants for all eight porphyrias. Here we describe the overall objectives and the initial efforts to validate pathogenic and benign variants in the respective heme biosynthetic genes causing the AHPs.
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http://dx.doi.org/10.1038/s41436-019-0537-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229570PMC
November 2019
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