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Symposia

Symposium Monday 20 May 2019 - New developments in olddiseases

Vitamin D for conditions other than bone disease: An update ofthe evidence

H. MorrisQUMPRC, School of Pharmacy and Medical Sciences, University of SouthAustralia, Adelaide, Australia

The well characterized endocrine pathway of vitamin D metab-olism and its activities are solely responsible for vitamin D regulationof plasma calcium and phosphate homeostasis with a requirement of20 nmol/L of plasma 25-hydroxyvitamin D (25D) to generateadequate levels of plasma 1,25-dihydroxyvitamin D (1,25D). How-ever higher levels of 25D, (N50 nmol/L), are required to reduce therisk of numerous conditions including premature mortality, infec-tious diseases, maternal outcomes, epithelial cancers and osteopo-rotic fractures. Current data are consistent with the mechanism ofhigher plasma 25D levels being required for metabolism in non-renaltissues to exert autocrine actions. While most of the original data foradequate vitamin D levels decreasing risk of disease was based onassociation studies, more recent evidence has now improved thetheir quality to the highest levels. These include randomizedcontrolled trial (RCT), Mendelian Randomization and long termobservational study data. Probably the best data exist for adequatevitamin D reducing the risk of premature mortality. These includerandomized control trial (RCT) of vitamin D and calcium over some3 years, Mendelian Randomization data indicating that vitamin Ddeficiency below the level of 50 nmol/L is causal for prematuremortality and observational data over some 30 years. A controlledtrial of vitamin D supplementation based on attendance at one oftwo clinics, indicated that supplementation reduced the risk ofadverse outcomes of pregnancy by 70% in a population of womenwith a 65% chance of serum 25D below 50 nmol/L. Meta-analysis ofRCT of vitamin D as adjunct therapy for tuberculosis indicated a 20%increase in sputum smear or culture conversions and 30% decrease inzones of chest X-rays. Observational data indicate that the risk ofdeath for breast, prostate and colon cancer patients diagnosed with aserum 25D level N 75 nmol/L is reduced by 50% compare with suchcancer patients diagnosed with serum 25D b 50 nmol/L. Much of thepublished clinical data on the efficacy of vitamin D on disease riskhas been derived from poorly conducted trials and thereforecontroversy remains on the true requirements for this essentialnutrient. However over time studies, which have identified vitaminD deficiency prior to supplementation, have found beneficial effects.There are no data indicating that those with an adequate vitamin Dstatus benefit from further vitamin D supplementation.

doi:10.1016/j.cca.2019.03.1416


New diabetes treatments and the role of the laboratory

S. AtkinWeill Cornell Medicine Qatar, Qatar

The new Standards of Medical Care in Diabetes 2018 emphasisethe use of metformin as a first line agent for the treatment of type 2diabetes. It is recommended that subsequent second line therapy beinitiated after 3 months if glycaemic targets have not been met,depending upon the presence of atherosclerotic cardiovasculardisease (ASCVD); if no ASCVD is present, is there a compelling needto minimize hypoglycaemia, or weight loss or cost? Second and thirdline antihyperglycemic therapy may be indicated, this requiring apatient-centred approach with drug choice dependent upon efficacy,hypoglycemic risk, a history of ASCVD, weight and consideration ofthe side effect profile. Such oral therapies may include SGLT2inhibitors, pioglitazone, DPP4 inhibitors and sulphonylurea agents.It is now recommended that the first line injectable agent be a GLP1-receptor agonist rather than insulin but that, if insulin is to beinitiated, then an insulin with a lower risk of hypoglycaemia isadvocated. The new guidelines will be reviewed together with a briefoverview of the differing antihyperglycemic agents available, theirmode of action and the potential impact that this may have on thelaboratory with, for example, the recommendation for periodicmeasurement of B12 with metformin, the need to tailor therapy torenal function and to monitor the side effect profile.

doi:10.1016/j.cca.2019.03.1417


Old and new biomarkers for kidney disease

E. CavalierClinical Chemistry, University of Liège, CHU de Liège, Belgium

0009-8981/$ – see front matter

Clinica Chimica Acta 493 (2019) S733–S760

Contents lists available at SciVerse ScienceDirect

Clinica Chimica Acta

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In 1904, Otto Folin published a method for urine creatininedetermination using the Jaffe reaction. Today, serum creatinine (SCr)remains one of the most frequently requested tests in laboratorymedicine but it suffers from a lack of sensitivity to detect early stagesof CKD and its analytical determination is prone to many interfer-ences. Besides automation, major changes in Scr measurement arethe possibility to run enzymatic methods and the use of standardsdetermined by isotope dilution mass spectrometry (IDMS). Enzy-matic methods have been proposed to overcome the lack ofspecificity of Jaffe ones, but they remain little used, mainly becauseof the cost. They are however the only ones to be able to measure Scrconcentration in the low range. SRM 967a is now available tostandardize SCr assays. Large IVD companies now propose stan-dardized reagents, but this is not necessarily the case for smallerones. A large number of formulas have been published to estimateGFR based on Scr concentration. If they may be useful in clinicalpractice to classify patients according to GFR stages, they can bebiased in specific populations and their imprecision is quite high.Measurement of GFR with a reference method, like iohexolclearance, is the only way to assess GFR and should be performed,for example, in patients presenting an unexplained increase of Scr,in living kidney donors, in children ongoing chemotherapy and inpatients for whom serum Scr does not reflect GFR (obese, anorectic,paraplegics…). Plasma cystatin C (CysC) has been the Scr “chal-lenger” for years since it presents nice features compared to Scr(less interferences in the measurement, less variability according tomuscle mass, less gender and age difference, …). Fomulas based onCysC have also been published, but the cost of CysC and the lack ofevident added value refrain its use in clinical practice. Otherbiomarkers, like beta-trace protein have also been proposed, buthave been unable to show superiority over Scr. Combination ofmarkers have also been proposed in formulas to estimate GFR.Preliminary results with metabolomic makers showed promisingresults to estimate GFR but results need to be confirmed. Inconclusion, the old marker SCr still continues to be used and havenot been supplanted yet.

doi:10.1016/j.cca.2019.03.1418


What is new in cardiac markers?

P. Laitinenb, T.G. Cardiac MarkersaaEFLMbHUSLAB, Department of Clinical Chemistry, University of Helsinki,Helsinki, Finland

The task of EFLM Working Group Cardiac Markers was to performsurveys on the use and implementation of cardiac markers inEuropean countries.

WG Cardiac Markers has performed altogether three surveys. Thestudy was named CARdiac MArker Guideline Uptake in Europe(CARMAGUE) study. The latest survey was expanded to NorthAmerica to see if there are any differences between Europe and US/Canada. The results show that there are differences between Europeand North America in the use of cardiac markers as well as in theguideline adherence. The results have been published in severalpeer-reviewed articles.

WG used a web-based questionnaire, which was distributed toEuropean and North American biochemical societies for circulationto their membership. Questions covered cardiac biomarkers mea-sured, analytical methods used, decision thresholds and theirderivations, sampling strategies, repeat sample interval, use of rateof change and use of decision-making protocols, collaboration withclinicians, internal and external quality assurance. Results werecollated using a central database and analysed using comparativeand descriptive nonparametric statistics.

The results of the surveys show clearly that there is need toencourage proper dialogue and biomarker utilization betweenlaboratory professionals and clinicians, as results show that there isvery little co-operation. Laboratories should be encouraged to adoptevidence-based cutoffs utilizing the 99th percentile of troponin andcutoffs of other cardiac biomarkers. In addition, internal and externalquality assurance needs to be improved.

The work of WG Cardiac Markers showed that cardiac markersare not properly utilized in clinical and laboratory medicine, and thismight jeopardize healthcare and patient safety. EFLM Task GroupCardiac Markers continues performing surveys on the use andimplementation of cardiac markers to see if there is any improve-ment in guideline adherence.

doi:10.1016/j.cca.2019.03.1419

Symposium Monday 20 May 2019 - Point of care testing. Fromquality assurance strategies to clinical utility and patientoutcomes

20 years' experience of quality assurance strategies of a large andISO 22870 accredited POCT multiparameter network

P. OliverPOCT Unit, Department of Laboratory Medicine/La Paz UniversityHospital, Madrid, Spain

La Paz University Hospital is a tertiary public hospital located inMadrid that is considered a reference center for numerous special-ties. The Department of Laboratory Medicine includes a specific unitwhich has led the POCT network since 1998. From the beginning, aPOCT Committee was also created as a multidisciplinary group. ThisCommittee includes professionals from different areas such aslaboratory medicine, members of the hospital administration,physicians from medical and surgical services, representatives ofnursing personnel and staff from the IT department. The POCTproject has always been supported by the hospital Board of Directors.The role that IVD companies have played these 20 years has alsobeen relevant.

Currently, the POCT network includes 29 blood gas analysers, 2HbA1c devices and 4 glucometers, all accredited by ISO 22870.The POCT Unit also coordinates the other 262 glucometers locatedin different clinical settings throughout the hospital and 1 sweattest device installed in the Paediatric Pulmonology Department.

There are activities such as analysers monitoring, internal qualitycontrol or reporting of results that are performed 24 h per day, 7days a week. The emergency laboratory is responsible for theseactivities.

The creation of a homogenous POCT network for all clinicalsettings, always led by laboratory medicine and in accordance withthe ISO 22870 requirements, is based on three key areas: continuousimprovement, staff training and competency and quality assurance.

Abstracts / Clinica Chimica Acta 493 (2019) S733–S760

All of them are essential to improve the management of POCT andconsequently, patient care.

Within the continuous improvement, the quality indicatorsimplementation and monitoring are crucial. In POCT, and specificallywith a complex network, it is especially relevant to manage theindicators appropriately.

Regarding staff training and competency, we must consider boththe initial and the continuous operators training. Every test followsthe particular program established by the laboratory.

Concerning quality assurance, we take into account new testappropriateness evaluation, analytical quality specifications andother requirements selection, method performance verification andmonitoring of internal and external quality assurance.

Finally, in our experience, it is also crucial to carry out researchstudies on the clinical, operative and economic outcomes of POCT onpatient care and patient safety.

doi:10.1016/j.cca.2019.03.1420


Quality control and analytical performance specifications fordifferent clinical POCT settings. Should they be different?

S. SandbergNoklus, Haraldsplass Deaconess Hospital, Bergen, Norway

POCT is the most rapidly growing field in laboratory medicine.With increasing technological and analytical possibilities, an increas-ing number of analyses can now be carried out on POC instruments.Although the costs of POC instruments are less than hospitalinstruments, the number of users of POC instruments are muchlarger, ranging from wards in the hospitals, GP offices, nursinghomes, pharmacies and last but not least tests for self-measure-ments. With the increasing emphasis on patient empowerment, thisis a wanted development.

The ultimate goal of using POC testing is that patient outcomesshould be improved and/or that it should be more cost/effectivethan the use of conventional laboratory testing. To achieve this, therole of POCT in the different clinical settings as well as theresponsibility for introducing and manage the instruments and useof the instruments should be clearly defined. The main reason forusing a POC instrument is that a rapid result is more useful thanwaiting for a result from a central laboratory. An essential questionis therefore: Should performance specifications for POC instrumentsbe different from that of instruments in a central laboratory. Manywill say “yes”, but taking into account the different use of suchinstruments, performance specifications could probably be modi-fied. Many POC instruments are used for specific clinical settingsand one should therefore try to develop performance specificationsfor that setting, i.e. based on clinical outcomes. It is also probablethat time and location is an important quality factor and thatperformance specifications can be less strict if a result is providedrapidly – especially in cases where you would like to know if theresult is “very high” or “very low”; e.g. hypo- and hyperglycemia.However, if performance specifications for some POC measurementprocedures should be less stringent compared to the centrallaboratory, it is important that this is communicated to the usersof tests.

Quality control is a well-established routine in laboratorymedicine. Since POCT is carried out in a different environment withdifferent users and often with different performance specificationsand different types on inbuilt controls, we have to re-evaluate howand which types of quality control we should use. Little evidence isavailable for example for how often to use internal and externalquality control for POC instruments.

doi:10.1016/j.cca.2019.03.1421


Sensus student competition: Global education and innovation inPOCT

M. PrinsEindhoven University of Technology, The Netherlands

SensUs (www.sensus.org) is the annual international studentcompetition in the field of sensors for health. SensUs was founded in2016 and represents a novel way to stimulate education andinnovation in POCT.

Over the course of a year, teams of students from universities inEurope, Asia, North-America, and Africa develop innovative biosen-sor systems that target a real-world challenge. The theme of thecompetition changes annually. In 2018, the theme was antibioticsand the participating teams developed biosensors to detect vanco-mycin in a drop of blood. In 2019, the theme is rheumatism and allteams will detect adalimumab, an important anti-inflammatorybiological drug. During the SensUs Innovation Days, all teams cometo Eindhoven to demonstrate their prototypes and their businessmodels to the jury, companies, healthcare professionals, patients,and the general public.

This presentation will consist of two parts. In Part 1, a member ofthe SensUs Organization will explain the philosophy and approach ofthe competition, focusing on gained experiences, impact, and plansfor the upcoming years. In Part 2, a member of the winning team ofSensUs 2018 will explain how they designed and developed theirbiosensor and their business model, within the open-innovationspirit of the SensUs competition.

doi:10.1016/j.cca.2019.03.1422


Clinical utility of point of care testing in Africa

R. ErasmusFaculty of Medicine and Health Sciences, Stellenbosch University, CapeTown, South Africa

The need and availability of point-of-care testing (POCT)instruments and devices has grown significantly in recent yearswith ever more testing being carried out at the patient bedside.


Originally, most point-of-care tests were undertaken on patientswho were acutely unwell, when rapid test results were needed forclinical reasons. However, in recent times most POCTimplementations undertaken have been driven by economics andhelping to ensure that patient pathways work more efficiently.While POCT will help speed up the availability of results, it isimportant to ensure that the risk to the patient is minimised. Whenimplementing a POCT quality control (QC) strategy it is importantto balance the risk of harm to the patient with the stringency of theQC procedure applied. Africa, with its limited infrastructure andrural terrain is particularly suited to POCT. With the epidemic ofHIV,TB, Malaria and now Diabetes many countries in Africa haveestablished well structured screening pathways using POCT. WHOhas even come out with a document specifying the criteria for siteselection and unique internal and external quality programs havebeen set up. Whilst the number of clinical trials that have shownthe benefits of POCT are limited, POCT has come of age and willprovide an alternate form of testing in certain scenarios even moreso as the test menu continues to expand with more accurate andprecise instruments being manufactured. An interesting additionhas been molecular testing and its potential impact on personalizedmedicine.

doi:10.1016/j.cca.2019.03.1423

Symposium Monday 20 May 2019 - Principles and applications ofepigenetics

Basic principles of epigenetics: DNA methylation, histone modi-fications and non-coding RNAS

T. OzbenDepartment of Clinical Biochemistry, Medical Faculty, University ofAkdeniz, 07070 Antalya, Turkey

Heritable phenotype changes in gene expression not involvingalterations in the DNA sequence are defined as epigenetics.Epigenetic changes occur naturally during whole life span, and canbe influenced by several factors including age, environment, diet,lifestyle, and disease states. Epigenetic modifications play importantrole in cell differentiation and may cause damaging effects leading todiseases. DNA methylation, chromatin remodeling, histone modifi-cations, and non-coding RNAs are the major modifications causingepigenetic changes.

DNA methylation commonly refers to the covalent addition of amethyl group from the s-adenosylmethionine to the fifth carbon of thecytosine base catalysed by DNA methyltransferases resulting in 5-methylcytosine (5-mC), known as the “fifth base” of DNA. Methylgroups project into the major groove of DNA and inhibit transcription.Tissue-specific DNA methylation patterns exist in cancer, metabolic,autoimmune, and neurological diseases. Differentially methylatedregions (DMRs) identified by genome-wide methylation profilingmay be used as biomarkers or potential targets of epigenetic therapy.

Chromatin remodeling is highly implicated in epigenetics.Histones are principle components of chromatin and covalent post-translational epigenetic modification (PTM) to histone proteinsincluding methylation, phosphorylation, acetylation, ubiquitylation,and sumoylation can alter the structure of chromatin resulting intranscriptional activation or repression. Global histone modificationpatterns have been shown to be associated with various types ofcancers, many of which are regulated by natural components.

Histone deacetylase (HDACs) inhibitors are currently being devel-oped as anticancer agents.

A non-coding RNA (ncRNA) is a RNA molecule transcribed fromDNA, but not translated into proteins. Non-coding RNAs can be shortor long and are classified by their genomic origin and mechanism ofaction. Given the key importance of non-coding RNAs in cell biology,therapeutic approaches based on their targeting via diverse tools arenow under development and offer many advantages over classicalprotein-targeting therapies.

doi:10.1016/j.cca.2019.03.1424


Epigenetics in humans: From early development to aging

R.F. Pérezb, M.F. FragaaaCINN-CSIC, IUOPA, BOS-Oviedo University, ISPAbISPA, IUOPA

Epigenetic mechanisms have been well described during embry-onic development, in which extensive chromatin remodeling takesplace. However, postnatal life is also characterized by gradual (andsometimes sudden) changes in epigenetic marks. Research is neededin order to distinguish changes due to stochastic or environmentalfactors, giving rise to “epigenetic drift”, from those that constitutecontrolled biological processes. For instance, DNA methylationchanges during aging have been classically associated to those thatoccur during the development of cancer, providing a putative causallink between these two related processes. However, we haverecently demonstrated that loss of methylation occurs at distinctchromatin scenarios in aging and cancer by integrating differentepigenetic marks on a genome-wide scale, for multiple tissues.Moreover, it is also necessary to shed light on the epigenetic changesthat occur during early-life, because these could be functionallydifferent from those caused during adult aging. To this end, we haveperformed longitudinal genome-wide analyses of DNA methylationchanges during the first 10 years of life, to find that alterations aredrastically reduced after the first 5 years, and that these changescould be different to those that appear later on throughout life.Currently, we are embarked on several projects by which we seek todefine potential epigenetic mechanisms related to aging and aging-related diseases: analysing human cohorts in order to predict theonset of dementia by DNA methylation, using animal models tostudy the impact of aging on cognitive processes driven byepigenetic changes and studying aging-associated variability ofepigenetic marks at repetitive DNA elements.

doi:10.1016/j.cca.2019.03.1425


Epigenome-based treatment against cancer

V. Carafa, L. AltucciUniversity of Campania Luigi Vanvitelli, Italy


Human diseases are difficult to cure since it is hard to predict howpatients will respond to therapy. New tools and personalizedmedicine are needed to render therapies more efficient. The last20 years have been characterized by the flop of several drugs inadvanced clinical development, possibly due to the lack of knowl-edge of the molecular pathways that underlie their mechanism ofaction. Chromatin alterations have been related with both cause andprogression of tumors. Here, we identified a novel RIP1–SIRT/HAT1complex controlling survival and death via regulation of RIP1acetylation. Notwithstanding the increasing interest for sirtuinsmodulation in tumorigenesis, very little known is on their involve-ment in programmed cell death programs. A major goal of epi-drugdevelopment is to increase the therapeutic index and limitdevelopment of resistance. One attractive option is to combineanticancer effects with drugs able to prevent neoplasia. Here, wehave developed and report on a novel pan-SIRT inhibitor that altersHAT1/SIRT equilibrium in the RIP1 complex, showing bona fideanticancer-selective and cancer-preventive activities in vitro, ex vivo,and in vivo. Our work expands the current views in the drugdiscovery and might prove useful in patients who may benefit from arecurrence-preventive approach with low toxicity during follow-upphases and in cases of established cancer predisposition. Thus,targeting the newly identified RIP1 complex may represent anattractive novel paradigm in cancer treatment and prevention.

doi:10.1016/j.cca.2019.03.1426

Symposium Monday 20 May 2019 - Ethical issues in laboratorymedicine

Ethical issues in biomedical publication

M. O’kaneClinical Chemistry Laboratory, Altnagelvin Hospital, Western Health andSocial Care Trust, Londonderry, Ireland

Developments in clinical care are predicated on research studies,which are published in the biomedical literature. High ethicalstandards are important to ensure the quality of these publications,to retain public trust in science and the scientific basis of clinical careand to ensure that individuals receive credit for their ideas. Thisplaces heavy responsibilities on authors/researchers, editors, re-viewers and publishers alike. International bodies such as COPE,WAME, ICMJE have developed policies and guidance to ensure theintegrity of publications in biomedical journals. Issues that may ariseinclude plagiarism, redundant [duplicate] publication, fabricateddata, inappropriate attribution of authorship, undisclosed conflictsof interest [relating to the author, peer reviewer or editor], ethicalconcern about the conduct of the clinical research, appropriation ofan author's ideas by a reviewer. The era of open access publicationand a publishing business model whereby authors pay a fee forpublication has posed new challenges. In particular, there has beenthe growth of so called ‘predatory’ publishing which has resulted injournals being delisted as a result of questionable peer reviewprocesses.

doi:10.1016/j.cca.2019.03.1427

Symposium Monday 20 May 2019 - Ethical issues in laboratorymedicine

Personalized genomic medicine: Ethical considerations

J.J. Jonssona,b

aDepartment of Biochemistry and Molecular Biology, University ofIceland, Reykjavik, IcelandbDepartment of Genetics and Molecular Medicine, Landspitali – NationalUniversity Hospital, Reykjavik, Iceland

Personalized medicine is an approach for disease treatment andprevention based on individual variability in genes, environment,and lifestyle. Research in this field is typically done on largepopulations with big datasets of clinical information and variousomics-based laboratory studies. This setting can easily generateethical dilemmas.

At the same time, laboratory medicine physicians and specialistsface increasing responsibility in running complex testing requiringinterpretation based on the clinical situation. Demand for shortturnaround times as well as indirect and direct reporting to patientsalso brings the laboratory closer to the clinical interphase withintricate human interactions.

These developments make skills in ethics ever more important forclinical laboratory directors. Ethics is a discipline defined by its ownconcepts and techniques. Ethics is not about not doing anythingwrong. It is about making choices. Ethics enhances our ability to copewith uncertainty and make decisions.

There are four main areas where ethical dilemmas repeatedlycome up in research and the sprouting clinical practice of big datadriven personalized medicine: Additional incidental findings, con-sent, autonomy and privacy. Balancing the needs of personalizedmedicine and the principle of patients´ interests come first createstensions that often remains unsolved.

doi:10.1016/j.cca.2019.03.1428

SEQC Symposium Monday 20 May 2019 - New trends in thediagnosis of inborn errors of metabolism

Untargeted crossomics in a diagnostic setting

J. Jans, M. Willemsen, H. Haijes, P. Van Hasselt, M. Van De Ham, J.Gerrits, S. Fuchs, K. Van Gassen, B. Prinsen, M. De Sain- Van DerVelden, N. Verhoeven-DuifUniversity Medical Center Utrecht, The Netherlands

With unprecedented pace the number of recognized inbornerrors of metabolism (IEM) is expanding. Whereas whole exomesequencing (WES) and whole genome sequencing (WGS) have foundthere way into routine genetic diagnostic practice, advances indevelopment of generic metabolic diagnostic modalities seem to lagbehind. Since a few years, untargeted high resolution metabolomicsallows the parallel determination of N25,000 low molecular weightmetabolites – intermediates and final products of all pathways ofmetabolism in the body. An individual metabolic fingerprint can bedetermined in only three minutes. Untargeted metabolomics hasgreat potential to improve the yield and the speed of diagnostics ofIEM in individual patients.


We designed a workflow for untargeted metabolomics in driedblood spots (DBS) of individual patients. Briefly, DBS of patients wereanalysed using chip-based nanospray coupled to a Q-Exactive directinfusion high resolution mass spectrometer operating in bothpositive and negative mode with an m/z scan range of 70–600. Datawere processed using an in-house developed untargeted metabolo-mics pipeline written in R programming language, using HMDB foridentification. Z-scores were calculated and a metabolite selectionprocess was designed. We validated the diagnostic value ofuntargeted metabolomics using DBS of patients for whom regularmetabolic diagnostics did not result in a diagnosis and DBS ofpatients with novel genetic variants that are difficult to interpretbased on genetic information alone.

Finally, we have developed a fully integrated combined anduntargeted genetic-metabolic diagnostic workflow. Often, WESresults in many genes with variants. Most mutations in (novel)metabolic disorders are of the missense type that are difficult tointerpret and usually are classified as variants of uncertain clinicalsignificance (VUS) and, depending on filtering steps, often not evenreported. In some patients, the unfiltered list of genes with variantscan even exceed 100. Our crossomics approach prioritizes thesemissense mutations by utilizing untargeted metabolomics in DBS incombination with in silico-predicted metabolic surroundings of all(unfiltered) genes.

We propose that untargeted metabolomics should be performedin patients undergoing WES and anticipate that a combined geneticand metabolic approach will provide complementary informationand thereby speed up the diagnostics process and improve thediagnostic yield.

doi:10.1016/j.cca.2019.03.1429


Integrative approaches for the diagnosis of inborn errors ofmetabolism

H. Rochaa,baNewborn Screening, Metabolism and Genetics Unit, Human GeneticsDepartment of National Institute of Heath Doutor Ricardo Jorge, Porto,PortugalbComisión de Diagnóstico Perinatal de la Sociedad Española de Medicinade Laboratorio, Portugal

Inborn errors of metabolism (IEM) are a group of inheritedgenetic disorders affecting Human metabolism. Classically, thediagnosis is achieved through the detection of accumulated ordepleted relevant metabolites, in different body fluids, or throughenzyme/transporter activity measurements. For many years, this wasthe only available approach for the diagnosis of IEM. The picturestarted to change with the advances of molecular genetics in the 80's,that brought new possibilities to diagnose diseases in whose classicalbiochemical approaches are not efficient, being also very importantfor carrier detection and prenatal diagnosis. In the 90´s, NewbornScreening (NBS) for IEM changed dramatically with the introductionof tandem mass spectrometry, that allow the simultaneous quanti-fication of a large number of metabolites, enabling the pre-symptomatic detection of N30 IEM. More recently OMIC's approachesreached the clinic, generating and making available huge amounts ofbiochemical and molecular data. All these developments, from NBSto OMICs, raised new questions, namely how we can combine all

available diagnostic resources in order to reach the best diagnosticefficiency. Based on actual knowledge, it is accepted that the bestapproach depends on the disease/group of diseases we are lookingfor. Several examples will be presented illustrating the integration ofthe diagnostic approaches for different disease groups.

doi:10.1016/j.cca.2019.03.1430


Inborn errors of metabolism diagnosis in next generationsequencing era: Opportunities and difficulties

B. PerezCentro de Diagnóstico de Enfermedades Moleculares, Centro de BiologíaMolecular, CIBERER, IdiPaz, Universidad Autónoma de Madrid, Spain

Inborn errors of metabolism are a large group of rare disorders. Inspite of the fact many of the IMD are detected using biomarkers,genetic analysis should be mandatory for disease confirmation andmaking personalized therapy choices. Until five years ago, the goldstandard for making such genetic confirmations was gene-by-geneSanger sequencing. However, next generation sequencing (NGS),which is quicker and cheaper, is receiving increasing attention,particularly for locus-heterogeneous disorders (i.e. cobalamin disor-ders, hyperphenylalaninemia, peroxisomal disorders, lysosomaldefects etc.). In this work we report the strengths and weaknessesof the different types of DNA sequencing systems (targeted genepanels, clinical exome sequencing, whole exome sequencing orwhole genome sequencing) applied for confirmatory test followingthe detection of suspected inborn errors of metabolism in theSpanish newborn mass spectrometry screening program (NBS) andalso for genetic confirmation of cases detected after clinicalsuspicion. Regarding the samples form cases detected in the NBSprogram we were able to confirm the disease in the 70% of the cases.Furthermore, we were able to identify new genes associated toknown biochemical conditions (i.e. SLC7A2, DNAJC12, BCAT2), andmisdiagnosis cases (Combined malonic and methylmalonic aciduria).The remaining cases were false positive (carriers or cases with nopathogenic variants). The results allowed distinguishing those casesthat need treatment. In addition, the results obtained also haveexpanded our knowledge on phenotype-genotype correlation in IMDand have provided insight into association between” old diseases”and “new genes”. Our experience suggests that genetic analysis canbe used as confirmatory test´, but biochemical tests can be veryhelpful when a diagnosis is unclear, specifically when variant withclinical unclear significance are identified. Concerning disorderswhich are not included in the NBS program and lacking specificbiomarkers or specific clinical symptoms, the genetic analysis ismore relevant to confirm the diagnosis and to a greater extent todetect the specific gene in cases with atypical presentation of thedisease, such as glycogen storage disorders, congenital disorders ofglycosylation or mitochondrial diseases among others. In conclusion,genetic analysis may be requested for the identification of thespecific genetic disorder and in the future it could be used as analternative, rapid and reliable confirmatory test.

doi:10.1016/j.cca.2019.03.1431



Precision medicine meets newborn screening: The path forward

P. RinaldoBiochemical Genetics Laboratory, Department of Laboratory Medicineand Pathology, Mayo Clinic, Rochester, MN, USA

Newborn screening (NBS) is based upon laboratory testsperformed on a growing proportion of ~130 million children bornworldwide every year. Poor performance on a mass scale distresses amultitude of patients, and exposes both families and providers to anincreasing risk of psychosocial harm while incurring in unnecessaryexpenses. Our multidisciplinary team is focused on the creation ofhigh-throughput post-analytical interpretive tools to improve NBSperformance. Our goal is to achieve a near-zero false positive rate(FPR), which is the proposed definition of precision newbornscreening. Collaborative Laboratory Integrated Reports (CLIR 2.12;https://clir.mayo.edu) is a web application that maintains aninteractive database of laboratory results from multiple sites. TheCLIR tools are applicable to either the diagnosis of one condition or tothe differential diagnosis between two conditions with overlappingphenotypes. CLIR's defining characteristics are the replacement ofanalyte cutoff values with condition-specific degree of overlapbetween cumulative reference and disease ranges, and the integra-tion of primary markers with all informative permutations of ratios.An additional and unique feature of CLIR is the replacement ofconventional reference intervals with continuous, covariate-adjusted(age, birth weight, sex) moving percentiles. Harmonization bylocation is also routinely possible. Access to CLIR is freely availableto qualified users worldwide willing to share reference data andprofiles of positive cases in advance of being given access to thewebsite. The goal of collaboration and data sharing is to sustain aconstantly evolving, and improving, clinical validation. The type ofstatistical modeling that takes place within CLIR requires big data,and indeed a willingness to evaluate the concept that referenceintervals could be defined by “recycling” and harmonizing vastamounts (N N 1 M) of normal screening test results from a multitudeof sources. As an example, over a two year period (N= 116,469) wehave achieved a FPR of 0.0009% and a PPV of 87% for NBS of threelysosomal disorders. FPR reduction for non MS/MS conditionsbetween 50% and 80% is also achievable.

doi:10.1016/j.cca.2019.03.1432

Viewpoint Monday 20 May 2019 - Who should lead a medicallaboratory?

Who should lead a medical laboratory? The case for thetechnologist (Biomedical Laboratory Scientist)

M.N. RoaldMøre and Romsdal Hospital Trust, Ålesund Hospital, Medical Biochem-istry Ålesund, Norway

Professions in medical laboratories are numerous and there is nointernationally accepted standardization of these professions or theirtitles. Biomedical Laboratory Scientist (BLS) is the internationallyaccepted title of a profession with a generalist medical laboratory

education, with a bachelor's or higher degree. The title of theprofession is previously, and in some countries still, known asBiomedical/Medical Laboratory Technologists or Biomedical/MedicalTechnologists, as indeed the title of this presentation demonstrates.There are still differences between countries/regions regarding BLSsbasic education and the opportunity for employment in differentpositions.

In Norway, we have mainly two professions in the medicallaboratories, medical physicians with a general medical degree andthereafter specialized in one of the medical laboratory specialities(approximately 100–150 in total within medical biochemistry), andBiomedical Laboratory Scientists (approximately 3000–3500 withinmedical biochemistry). Most of these laboratories are in hospitalsand serve both inpatients, outpatients and patients from thecommunity.

The first BLS's started holding positions as leaders in medicallaboratories in Norway N25 years ago. Now, a large majority ofmedical laboratories are lead by BLSs, on management levels fromlocal hospital laboratories, larger laboratory departments and up tomanaging diagnostic clinics consisting of all laboratory specialitiesand in some cases also including radiology.

As a leader, you are responsible for utilizing and organising themedical laboratory within your available resources. You cannot,and shall not, do all the work yourself, but create these resultsthrough others. A good leader enables employees to do their job. Itis useful with an educational background and professionalexperience from the medical laboratory. But a leader is a servant.A servant for the employees, cultivating them, clearing obstaclesout of the way and enabling them to do their job. If your desireand competencies is to communicate with clinicians and work withprofessional research and development, you should leave themanagement part of the job to others. Let those who have adesire to lead take that on. It is a full-time job and the employeesdeserve a leader.

doi:10.1016/j.cca.2019.03.1433


The leadership challenge to leadership

G. WieringaBolton NHS Foundation Trust, UK

Who should lead? The best person. The person who can providethe vision and strategy to deliver laboratory medicine's contributionto best care and better health. It will be the person with the rightknowledge, skills and competence. He/she focuses high qualityclinical, scientific and technical services on enhanced clinical,financial and organisational outcomes; provides empathic andempowering support for laboratory medicine's diverse work forceand their education/training; communicates widely beyond thelaboratory to enhance our contribution to patient care and popula-tion health; possesses the technical skills that allow technologyinnovation to be identified and exploited; drives research anddevelopment. When will we have the best person? When we haveappointed him/her. The challenge is recognizing that individual and,in this regard, there may be much to be learned from the scope,expectations, quality and safety of laboratory medicine services andtheir leaders across country borders. Recognition necessarily extendsto minimum guarantors for patients such as qualifications,


registration/ regulation status, evidence of continuous professionaldevelopment but beyond such baseline assurances are the leadershipattributes of the individual to manage and direct that often evolveover time at different rates in different environments. Perhaps theleadership challenge for professional organizations is to identify andsupport the right individuals by helping to set the knowledge, skillsand competence benchmarks that ensure equity of access. The bestleader should never be the person we never had.

doi:10.1016/j.cca.2019.03.1434


The case for the physician

M. NeumaierInstitute for Clinical Chemistry, Medical Faculty Mannheim of Heidel-berg University, D-68167 Mannheim, Germany

Medical laboratories provide actionable health information andsupport the clinical decision-making in the greater majority of alldecisions that are made in therapeutic medicine. As the famousGerman internist and nephrologist Franz Volhard said in the early20th century: “Before therapy, the gods have put the diagnosis”.

Laboratory Medicine findings are characterized by two centralskills, i.e. an expert technical proficiency for the valid and precise testresult and a profound medical knowledge to navigate throughdifferential diagnoses. Depending on where we look, medical labsmay harbour a single or several different in-vitro diagnosticspecialties including Clinical Chemistry, Microbiology, Haematology,Histopathology or Genetics raising the question what type ofprofessional skills are required to run a diagnostic laboratory.Considering EFLM, approximately 40% of her members are laboratoryphysicians, while 60% are non-medical laboratory specialists withvarious scientific backgrounds in Biochemistry, Biology, Pharmacol-ogy and Toxicology etc.. The easiest argument why a medicallaboratory should be run by a laboratory physician is the often-citednotion that Laboratory Medicine is a medical profession. Similarly, aphysician's comprehensive medical education would warrant validmedical interpretation. Finally, a medical degree of the laboratoryhead assures proper recognition during the medical dialogue withthe clinician for the patient's benefit.

An ever growing number of laboratory biomarkers e.g. fromsimple electrolytes to complex epigenetic patterns adds to thecomplexity of both choosing lab requests and managing lab resultsfor the physician at the bedside. Increasing technical standardization,automation and closed kit reagents will further diminish the need formethodological and analytical skills in the future, and near-patientdiagnostics may solve major pre-analytical problems. This leaves themedical interpretation as the major service best communicated/discussed by a laboratory physician, particularly where digitalizationwill increasingly integrate anamnestic, clinical and diagnostic data.Still, it is undisputed that non-medical laboratory specialists canhave extraordinary medical knowledge enabling them to give therequired and proper support asked for by the therapist.

doi:10.1016/j.cca.2019.03.1435

Viewpoint Monday 20 May 2019 - Meet the Thyroid Expert

Meet the thyroid expert

D. GrusonCliniques Universitaires Saint Luc, Belgium

Thyroid function tests play a pivotal role in thyroid practices andare precious companions for physicians. Evolution of assays (TSH,thyroid hormones, thyroglobulin and thyroid autoantibodies) ispermanent and involves automation, highly sensitive assays andmass spectrometry based methods. Laboratorians are key actors todefine the decision limits and for the validation of novel methods.Furthermore, several standardization efforts are also ongoing andwill impact the performances of the assays.

However, thyroid function tests could be vulnerable to differenttypes of interference that can impact clinical decision. Potentialinterferences in thyroid function testing should always besuspected whenever clinical or biochemical discrepancies arise.Their identification relies on additional laboratory tests that includeassay method comparison, dilution procedures, blocking reagentsstudies, and polyethylene glycol precipitation. Interdisciplinaryexchanges with the clinical teams are mandatory to identify suchinterferences.

doi:10.1016/j.cca.2019.03.1436

Symposium Tuesday 21 May 2019 - Financing LaboratoryMedicine

Broadening access for innovative diagnostic solutions

N. FarkasCENTIVIS AG - Diagnostics Value Captured, Switzerland

In Vitro Diagnostics (IVD) operating environment is changingrapidly and getting more complex to operate in. Regulators andPayers increase policy scrutiny, diagnostic solutions require more,and better clinical evidence and digital diagnostic solutions challengethe status quo. On the other hand, health care systems facesignificant cost pressure, innovation cycles are getting shorter andsolutions more technologically advanced.

The question emerges: how can patients benefit from broadaccess to new innovative diagnostic solutions in such a rapidlychanging environment?

The presentation will briefly cover key trends, impacting IVDbusiness and will focus on the emerging global importance of Payersin product development and commercialization.

We will introduce the main Payer challenges, potential solutionsand in a simple, 5-step framework we will cover the key successcriteria of successfully securing reimbursement, leading to broadpatient access, adoption.

Before the final Q&A session, industry leading market access bestpractices will be demonstrated based on real-life company andproduct examples.

doi:10.1016/j.cca.2019.03.1437


Symposium Tuesday 21 May 2019 - Advances in in-vitrofertilisation

The role of the laboratory in IVF success

J. HreinssonMinerva Medica, Uppsala, Sweden

Introduction

Huge developments have been made in the IVF laboratory, whichhave had a great impact on treatment practices and results, even at anational level. Examples are the implementation of ultra-rapidcryopreservation, vitrification, revolutionizing embryo cryopreserva-tion and oocyte donation. Time-lapse photography is increasing ourunderstanding of human embryo development and PreimplantationGenetic Testing is improving success rates and reducing negativeoutcome effects.

Aim and methods

Give an overview over how improvements in laboratory technol-ogy impact the field of assisted reproduction.

Surveys of embryological laboratories in the Nordic countries anda literature review were performed.

Results and conclusion

IVF-laboratories in the Nordic countries and the rest of the worldhave radically changed their methodology so that by 2017, 98% ofNordic IVF-clinics were applying vitrification instead of controlledrate cooling. This change has had a tremendous effect on the resultsfrom assisted reproduction treatments. In 2016 according to theSwedish IVF-registry, birth rates were higher in cycles replacingvitrified/warmed embryos then when using fresh embryos (31% vs29%). In some countries, a majority of transfer cycles is performedusing cryostored embryos instead of fresh, dramatically reducingside-effects of treatment such as ovarian hyperstimulationsyndrome.

Time-lapse photography allows continuous monitoring ofembryo development during culture. Studies show an improve-ment in results when using this new technique while computer-ized scoring of embryo quality is a decision support for theembryologist and may replace traditional microscopic evaluation inyears to come.

Embryo biopsy during in-vitro culture coupled with geneticanalysis allows diagnosis of inheritable disease and selection ofchromosomally normal embryos for transfer. Replacing chromo-somally normal embryos has been shown to improve pregnancyrates, giving implantation rates of up to 50% while reducing therisk for miscarriage to as low as 5%, otherwise observed at a rateof 15–20%.

The IVF-laboratory plays a key role in the success of IVF-treatment and the importance of technical development, diagnosticsand genetic analysis is by now central to the development of thewhole field.

doi:10.1016/j.cca.2019.03.1438

Symposium Tuesday 21 May 2019 - Advances in in-vitrofertilisation

Ovarian stimulation and monitoring

J.I. Olofssona,b

aAbbott EPD, Basel, SwitzerlandbKarolinska Institutet, Stockholm, Sweden

Methods using exogenous gonadotropins for ovarian stimulationprior to assisted fertilisation has since its first description during early1970´s been employed to induce development of multiple dominantfollicles to obtain mature oocytes, thereby improving chances forconception after IVF/ ICSI. Until recently, the prevailing view of anoptimal oocyte yield has been that the results deteriorated at an eggharvest over 15, however, the outcome of recent large registry-basedstudies has demonstrated that when the results of cumulativetreatments using also surplus cryopreserved embryos are also included,ie results per egg collection, a number of up to 20 eggs or more, willfurther improve chance of obtaining a live birth. Prediction of ovarianresponse category today is mainly applied by using the vaginalultrasound and counting the ovarian antral follicle (AFC) or serumanti-mullerian hormone levels (AMH) in the early follicle phase. Bothrelate to thenumberof antral folliclespresent at any timeand the sourcefor the number of dominant follicles that could grow in results to theapplication of exogenous FSH. The use of short acting GnRH antagoniststo prevent premature ovulation or luteinization has today largelyreplaced the earlier role played by pituitary downregulation by GnRHagonist treatment, mainly due to higher patient friendliness with fewerside effects. An additional reason is also the possibility of inducing finaleggmaturation with an GnRH agonist instead of hCG and thus avoidingovarian overstimulation syndrome (OHSS) even at high numbers ofoocytes. The good results with higher pregnancy outcomes usingvitrified embryos has made possible segmentation of treatment cycleswhereby all good quality embryos are frozen, whereafter a thawed/warmed blastocyst can be transferred at a later calm stage. Thesupraphysiological levels of steroids after ovarian stimulation inhibitspituitary LH secretion, resulting in insufficient stimulation of corporalutea and a less receptive endometrium. Therefore, luteal phase supportusing progestogens is indicated. Since oral delivery of progesteroneleads to varying levels of absorption and high first-pass metabolism inthe liver, resulting in uncertain effects, injections or vaginal route ofdelivery is commonly used. However, vaginally administered micron-izedprogesterone is associatedwith its ownadministration-related sideeffects, such as interference with coitus, vaginal bleeding, irritation anddischarge. A more convenient treatment paradigm for luteal phasesupport has recently been demonstrated in two large randomizedcontrolled studies using oral dydrogesterone (progesterone shaped byUV light and transformed into an orally active form, retroprogesterone)showing similar pregnancy outcomes and safety results when com-pared to two different vaginal progesterone preparations. The EuropeanSociety of Human Reproduction and Embryology (ESHRE) will for thefirst time, in early 2019, publish a guideline with evidence-basedinformation on the different options for ovarian stimulation in IVF/ICSIwhere optimal ovarian response, live birth rates, safety, patientcompliance and individualization will also be considered.

doi:10.1016/j.cca.2019.03.1439


Symposium Tuesday 21 May 2019 - A new era in communicatingdiagnostics data to patients

Personalized communication of results to patients

I. WatsonUniversity Hospital Aintree, Liverpool, UK

The empowered patient is with us and want and expect toparticipate actively in their care, a significant element for many suchpatients are the investigations that are used to diagnose, monitor andintervene in their care.

Some countries have to a greater or lesser extent enabled patientsto directly access their medical records and this is an increasingtrend; though this begs the question as to how readily theycomprehend the information available to them? There is clearevidence that while patients may feel they understand the diseaserisks and their results that is often not the case to the detriment oftheir concordance with the agreed treatment plan. There is alsoevidence that discussions with a qualified healthcare professionalgreatly improves matters, however there is a significant timepressure of patient-facing staff.

In relation to laboratory medicine the same issues apply and forthose who are poorly numerate, and much of laboratory medicinedata requires numeracy, then the patient's ability to understand isfurther undermined. There is developing interest in specialists inlaboratory medicine (SpLM) engaging in this area of knowledgemanagement in a structured approach within the healthcare team.

The desirable paradigm is for a tripartite relationship between thepatient, their physician and the specialist in laboratory medicine andfor the SpLM to add context specific comments to reports forpatients, these necessarily must be consistent with the overall careplan and the supervising clinician. This is a developing area in whichthe method of data presentation has been shown to impact oncomprehension and similarly for any added narratives and currentideas will be explored.

The opportunity to positively engage in a new facet of deliveringa patient-focused laboratory medicine service is clearly there and isneglected at our peril!

doi:10.1016/j.cca.2019.03.1440


Classification and benchmarking apps for patients andprofessionals

S. Jovičića,baCenter for Medical Biochemistry, Clinical Center of Serbia, Belgrade,SerbiabDepartment for Medical Biochemistry, Faculty of Pharmacy, Universityof Belgrade, Belgrade, Serbia

The rapid increase of the global use of smartphones and theintroduction of their software platforms enabled designing specialpurpose applications – mobile applications (apps). Many of theseapps are used for delivering health interventions thanks to theiraccessibility to clinicians and patients. However, evaluation of thequality of health related apps is challenging. Governments do notregulate the content of mobile health apps unless they function as

part of a medical device. Quality in the context of an app storetypically refers to the app's user interface design and the perfor-mance, and stability of the software program. In the literature, therehave been many attempts to evaluate health related apps targeted atconsumers. A multidimensional tool for classifying and rating thequality of mobile health apps – Mobile App Rating Scale (MARS) isone of them. The MARS app quality criteria cover engagement,functionality, aesthetics, and information quality of the app content.We performed the analysis of the number and quality of smartphoneapps available in the two most popular app stores using in any waylaboratory medicine data. Seven categories were distinguished: 1)apps that offer medical advice about symptoms and health querieswith the possibility to upload laboratory test results, which can beseen, stored and shared; 2) reference ranges of selected analysis withbasic information about the causes of increase or decrease designedfor patients; 3) quick reference for laboratory tests for medicalstudents and doctors; 4) apps for monitoring the state of user'shealth through a wide range of health parameters, including glucoseand/or cholesterol as laboratory data, 5) apps that provide access topatients' laboratory results to physicians; 6) apps that enablepatients to access their laboratory test results directly from thediagnostic center; and 7) electronic health records apps that includelaboratory test results. The analysis of MARS score values revealedthe poorest performance and quality of the apps intended forpatients, with significant issues of security of personal informationused by the apps, and the questionable affiliation of developers,without referencing the source of information cited.

doi:10.1016/j.cca.2019.03.1441


Electronic apps and medical diagnostics data management

K. AdeliUniversity of Toronto, The Hospital for Sick Children, Canada

Laboratory medicine is a domain which offers a unique opportu-nity to analyze objective patient laboratory data and enable readycommunication to both healthcare workers as well as patients. Inrecent years, an increasing number of web-based and mobileapplications has been developed to improve access to laboratorytest information and test result interpretation. They range fromsimple apps that provide reference lab value information to complexmedical diagnostics data management. As examples, the “eLab”developed by Tru-Solutions Inc. is a comprehensive medicaldiagnostic center and lab management software that provides a userfriendly interface and access control. It is linked iMedDx.com toallow flexible patient search and selection and includes an eLabDashboard on mobile/tablet, allowing patients and labs/hospitalsaccess to lab reports online. The Davis's Laboratory & DiagnosticTests medical app provides another useful app with a wide-breadthof tests, as well as guidance on how to counsel and collect tests. Theapp is available on multiple platforms including the iPhone/iPad,Android and Blackberry. The “LabGear” is a medical lab reference appproviding a pocket tool for medical laboratory test and is integratedwith MedCalc with normal lab value reference information for over200+ lab tests. There are several other medical apps that providereference lab values including CALIPER, MedRef, Normal Lab Values,and Lab Tests. The CALIPER App has been developed in ourlaboratory for paediatricians, family physicians, and other healthcareworkers worldwide. It is a user friendly and easy tool to assess a


child's laboratory test results using the latest reference valuedatabase developed based on a study of thousands of healthychildren and adolescents. The CALIPER apps allow paediatricians &family physicians to interpret laboratory test results for over 170medical laboratory tests in children and adolescents using acomprehensive database of paediatric reference standards. WEBApp: https://caliper.research.sickkids.ca/#/ In this presentation, I willreview some of the key web and mobile resources in laboratorymedicine and will discuss the critical importance of electronic appsin management of medical diagnostics data.

doi:10.1016/j.cca.2019.03.1442


Online resources for patients and healthcare professionals

T. PillayUniversity of Pretoria, National Health Laboratory Service, University ofCape Town, South Africa

Patients and healthcare professionals can access a vast array ofhealthcare information on the internet. Patients are increasinglyaccessing websites offering disease-specific information which iscontributing immensely to implementing the “participatory” philos-ophy of “P4 medicine”. In addition, patients can also accessprofessional information, especially from open-access scientificjournal publications. Online resources can also be used for commu-nication between patients and between patients and health careproviders. This can also be useful for disease management and this isespecially noteworthy in diabetes and asthma where frequentmonitoring can lead to early detection of impending crises. Onlineresources are also valuable for patients with extremely rareconditions eg. rare inborn errors of metabolism or other geneticdisorders where experiences can be shared with other patients orhealthcare providers across the world.

In laboratory medicine, Lab tests online, Labs Are Vital and KnowPathology, Know Healthcare have gained prominence as resourcesthat patients can access to gain specific information about clinicallaboratory tests. Lab Tests Online was designed to help patients andcaregivers understand the many laboratory tests that are a vital partof medical care and to understand the meaning and implications ofresults. Labs Are Vital began as an online community to supportpathologists and laboratory professionals worldwide to elevate therole and reputation of pathology and laboratory medicine in healthcare. Know Pathology, Know Healthcare is an initiative of PathologyAwareness Australia.

Social media platforms are also important in the scope of portalsaccessible to both patients and health-care professions alike. Patientsand healthcare professionals can obtain real-time updates on themajormicroblogging platforms such as Twitter and Facebook. Healthcareprofessionals can engage in case discussions, research collaborations,medical education and crowdsourcing/crowdfunding and likewisewithpatient groups. It is clear that the use of online resources will increaseand grow in sophistication, especially in this era of Web 2.0.

doi:10.1016/j.cca.2019.03.1443

Symposium Tuesday 21 May 2019 - Stroke and CNS biomarkers inclinical practice

Are stroke biomarkers ready for research and clinical use? Focuson the pre-analytical, analytical and post-analytical variability

K. MakrisClinical Biochemistry Department-KAT General Hospital, Greece

Currently Computed Tomography (CT) brain imaging is routinelyused for confirming the diagnosis of an acute stroke (AS) anddistinguishing ischemia (IS) from haemorrhage (HS). Althoughreliable, CT scan is not available in every hospital, especially in theremote areas of low-middle income countries. It is used to diagnoseAS and exclude a HS but has very poor sensitivity to diagnose IS. Onthe other hand, Magnetic Resonance Imaging (MRI) has morereliability than a CT scan for acute diagnosis and differentiation ofstroke but is very expensive and not available at all emergencydepartments. Potential limitations include, time consuming, cost,availability issues and variation in the analyses of radiologicalimages.

Blood biomarkers may offer a reliable, rapid and a cost-effectiveway for AS management. Research has revealed several bloodbiomarkers associated with different pathophysiological pathwaysof stroke, to be potentially useful in its clinical management. Certainbiomarker combinations might help in the diagnosis, prognosis,differentiation, selection of treatment and monitoring of patientswith AS. Thus, the development and validation of a blood basedbiomarker approach with high sensitivity and specificity that willeffectively distinguish IS from HS in acute settings is a high prioritysince it will assist clinicians to intervene faster and offer bettertreatment to AS patients. Unfortunately, until today there is nodefined role for their use in the care of patients with acutecerebrovascular disease.

Challenges in the identification of clinically useful strokebiomarkers, include specificity to brain tissue, ability to pass-throughthe blood–brain barrier, correlation between functional symptomsand volume and location of injured tissue. Limitations also includethe incomplete analytical validation and total lack of standardizationof the assays that have been used in most of the research studies,that limits the value of systematic reviews and metaanalyses. Theresult is that most biomarkers exhibit variable sensitivity andspecificity. Moreover, there are significant gaps in knowledge forthe preanalytical and the biological variability for the majority of theinvestigated biomarkers that need to be addressed with futurestudies.

doi:10.1016/j.cca.2019.03.1444


Guiding stroke therapy with the use of blood biomarkers

A. BustamanteVall d'Hebron Institute of Research (VHIR), Spain

From prevention to acute-phase treatment, personalized medi-cine have not shown a clear role in stroke so far. Despite many yearsof research and promising results, no biomarker is used specifically


for stroke care in clinical practice. In this session, we propose the useof blood biomarkers as a promising tool for a personalized approachto individual management of stroke, starting with primary preven-tion, for screening and management of the main stroke etiologies(namely atherosclerosis, atrial fibrillation and small vessel disease).

Once stroke occurred, blood biomarkers might help in themanagement of the acute situation. In the last years, two majoradvances, pre-hospital thrombolysis and endovascular therapies,have dramatically change acute stroke care. Blood biomarkersmeasurement could add in acute stroke management, in bothselecting patients at the pre-hospital level, as well as guidingreperfusion therapies to evaluate efficacy and safety, by guidingintravenous thrombolysis or allowing an accurate selection ofcandidates to endovascular therapies. In a more ambitious scenario,a blood biomarkers' panel might even be used for the pre-hospitaldifferentiation between ischemic and hemorrhagic stroke, whichwould allow a pre-hospital individualized treatment.

After the acute phase, patient's care in stroke units might be alsoindividualized and improved with biomarkers. Prediction of strokeoutcome and complications, such as cardiac decompensations or post-stroke infections, have been done with blood biomarkers, and severalgroups are working in the translation of this prediction into a bettercare after stroke. In addition, in strokes of undetermined etiology, theuse of blood biomarkers represents an alternative tool to guide furtherdiagnostic workup, or even to guide secondary prevention.

doi:10.1016/j.cca.2019.03.1445


CSF xanthochromia in the investigation of suspected subarach-noid haemorrhage (SAH)

G. BurrowsStockport NHS Foundation Trust, UK

Subarachnoid haemorrhage (SAH) is bleeding into the subarach-noid space and is managed as an emergency. The most commoncause of non-traumatic SAH is intracranial aneurysm. Most patientspresent with a severe, sudden headache, which may be associatedwith nausea, vomiting, loss of consciousness or meningism. A CTscan is the 1st line test (sensitive in almost 100% within the first 6 hfrom the headache onset; but only approximately 58% by Day 5). Aclinical suspicion of SAH with a negative CT scan requires a lumbarpuncture (LP) to look for CSF blood.

Following a bleed into the CSF, the oxyhaemoglobin from the redcells is converted to bilirubin, which gives the CSF a yellowdiscolouration (xanthochromia). This should not be assessed visuallyas it is unreliable and assessor dependent. The recommendedmethod is spectrophotometry, measuring absorbance at 476 mm.CSF bilirubin may not be present until 12 h after a bleed, but may bepresent for up to 2 weeks. As bilirubin is destroyed by light, clearsampling and transport requirements must be met; these recom-mendations will be shared.

The interpretation of the results of CSF analysis of protein, bilirubinand oxyhaemoglobin (and associated serum testing for bilirubin andprotein)will be discussed using the guidelines developed and amendedby the UK NEQAS Specialist Advisory Group for External QualityAssurance of CSF Proteins and Biochemistry. The potential pitfalls of

CSF xanthochromia analysis and the use of the flow chart will bedescribed. The role of the Quality Assurance Group in the standardiza-tion of xanthochromia testing will also be discussed, and some of thefrequent errors in the interpretation of results will be shared.

doi:10.1016/j.cca.2019.03.1446

SEQC Symposium Tuesday 21 May 2019 - EQA programs inSEQCML Spain. Almost 30 years' experience evaluating the TotalTesting Process

Achievement of quality specifications based on biological varia-tion in EQA. Is there a positive evolution?

C. Ricós-AguiláAnalytical Quality Commission of the Spanish Society of LaboratoryMedicine (SEQCML), External Quality Programs Committeeof theSEQCML

EQA is considered to be a pillar for attaining medical laboratorystandardization. The elements of EQA such as matrix of controls,target values assigned, data set studied, analytical property assessed,rationale and type of performance specifications (APS) used arebriefly revised.

The evolution of type of APS in EQA worldwide used from 1996 to2017 is shown. In 1996 the majority of EQA used state of the art,with extremely wide acceptability range, whereas 20 years laterbiological variation derived APS was the most widely option used.

The capability of EQA to evaluate participants depends on itsdesign and five categories of EQA were described. Its application inSpain over time is summarized, having presently a catalogue of 13programs of category 5 and one of category 1; the APS applied arealso shown.

Examples of results from the category 1 EQA scheme with APSderived from biological variation, running in Spain since 2015 aredepicted. They measure different analytical properties, such as % ofresults passing APS, total analytical error, inter-laboratory impreci-sion and bias. Comparisons among category 1 EQA-biologicalvariation derived APS results from various countries are made.

Possible reasons for the positive and negative impacts onstandardization seen in our experience are remarked.

doi:10.1016/j.cca.2019.03.1447


Quality specifications of Total Testing Process in EQA. Is there aninternational agreement?

P. Fernandez-CalleDepartment of Laboratory Medicine, Hospital Universitario La Paz,Madrid, Spain

To participate in an External Quality Assurance program (EQA) isa cornerstone in guaranteeing the accuracy of patients´ results andmoreover the adequate clinical decision making.


There are different types of EQA with different purposes. Some ofthem serve as regulatory compliance, some others have an importantrole in harmonizing and standardizing and others have an educa-tional aim. Therefore performance specifications are multiple andvaried, depending on the organizer and its intention.

After Milan Strategic Conference, a specific Task and Finish grouphas been created to deal with the harmonization of analyticalperformance specification for EQAs. Similarly, another Task andFinish group has been created to harmonize the performancespecification for the indicators of the Total Testing Process. Bothgroups elaborated a series of recommendations. A summary of theactions taken by different EQA organizers will be presented.

The importance of having harmonized analytical performancespecification is crucial due to its ability to accurately comparedifferent instruments and methodologies; and above all, because ofits impact on interchangeability of patients' results worldwide. Thelack of harmonization of analytical performance specification canlead to erroneous assessments of method comparability andanalytical performance. Consequently, it might constitute a limita-tion, especially when managing magnitudes with diagnostic cut-offincluded in international guidelines. The degree of harmonization ofanalytical performance specification reached by EQA organizers willbe also reviewed.

doi:10.1016/j.cca.2019.03.1448


Evolution of state-of-the-art over almost 30 years: Imprecisionand bias detection trough EQA. Interaction among EQA orga-nizers, IVD and participant laboratories

C. Perich AlsinaClinical Laboratory of the Hospital Vall d'Hebron de Barcelona, Spain

Nowadays, the state of the art is defined as the highest level ofanalytical performance technically achievable. Although the mainobjective of EQAS is to assess the performance of an assay from anindividual laboratory, using as quality indicator the allowable differencefrom a target, they also evaluatemethod performance (imprecision andbias), by comparing the results of the users of the same IVD.

30 year's evolution of methods, imprecision, bias and total errorof the Spanish laboratories are depicted, though examples of someanalytes. Moreover, we present the evolution of the state of the artover the years worldwide and the different activities carried out toimprove harmonization between clinical laboratories.

It explains advantages and limitations of the analytical qualityspecifications based on the state of the art used to evaluate theperformance of laboratories, depending on the EQAS design (regu-latory, educational, current performance).

Finally, we highlight the importance of the collaboration betweenprofessional laboratory organizations, IVD industry and EQAS toreach harmonization of the laboratory tests, in standardization ofmethods, eliminating obsolete methods, promoting the use ofcommutable calibrators and control materials.

doi:10.1016/j.cca.2019.03.1449


Evolution of quality indicators over N20 years. Looking back andforward

M. IbarzExtra-analytical Quality Commission, SEQCML, Patient Safety Commis-sion, SEQCML, Laboratory Medicine Department, University HospitalArnau de Vilanova, Lleida, Spain

Quality indicators are widely recognized as a necessary tool toassess the quality of clinical laboratory processes, facilitate thedecision-making and ensure patient safety.

The story of quality indicators implementation is reviewed, with afocus on the International Federation of Clinical Chemistry andLaboratory Medicine (IFCC) Quality Indicators Project and otherrelevant experiences.

The aims of quality indicators definition and their qualityspecifications are briefly discussed. Factors involved in the qualityof quality indicators results are presented and the importance of aworldwide harmonization is highlighted in order to enable theintercomparability among laboratories.

Furthermore, the results of the Extraanalytical Phase QualityAssessment Program of the Spanish Society of Laboratory Medicineare presented, from its beginnings in 1998 to the present. For themajority of the samples studied a decrease in preanalytical errorsamong the participating laboratories was observed throughout thestudy period. Lessons from these results are presented and discussed.

Finally, a glimpse into the future of quality indicators is taken,and into what the involvement of the organizers of external qualityassurance programs is expected to be.

doi:10.1016/j.cca.2019.03.1450

Viewpoint Tuesday 21 May 2019 - young scientist session

Publishing key points: How can I succeed publishing in topjournals?

A. SimundicDepartment of Medical Laboratory Diagnostics, University hospital SvetiDuh, Zagreb, Croatia

Writing scientific papers is a skill, that can be acquired. Definingthe audience and purpose of your paper is the first and veryimportant step. Once this is clear, one has to select a suitable journal.Quite often papers get rejected not because they are not good, butbecause they do not fall within the scope of the journal. Once journalis selected, author has to carefully read and follow journalInstructions to authors. There is nothing more offensive for anEditor-in-chief than to receive a paper which was not prepared inaccordance with the Instructions to authors of the Journal. Further-more, the style is very important. Generally speaking, the golden ruleis: the shorter, the better! Say what you have to say with a minimumnumber of words. Remember that a picture says more then athousand words. Thus, graphs and tables are always better that aplain text. Make sure you have communicated clearly your aims andaddressed all of the following questions: What was the study about?


Why do you think your study is important? Why do you think thatyour study deserves to be published? Has this been done by someoneelse already? Are you presenting something new, that has not beenpresented so far in the literature? What is the added value of yourwork? What impact will your work have on the science, professionand/or everyday routine work? Proper statistical analysis, firmconclusions which are based on your results, good literature citationsand many other details about your work are also very important.

Last, but not the least, reviewing a paper is as important aswriting a paper. You have done your best to prepare the paper andsubmit it to the journal and then you receive from the journal anumber of objections and criticism on your work. Certainly, readingreviewers remarks is probably the hardest thing an author has to do.However, revised paper is almost always much better than theoriginal. Remember, reviewers' remarks are here not to upset you,but to help you improve your work and help you get it published.

Obviously, there are many things that everyone who wants tohave his work published, needs to know. This lecture will provide aquick guidance on how to successfully prepare, submit, revise andpublish a scientific work in a desired journal.

doi:10.1016/j.cca.2019.03.1451


Young scientist: Career prospect, research, and networking

R. ShresthaFaculty of Health Sciences, Hokkaido University, Sapporo, Japan

Today's young scientists are the future of tomorrow's research.The challenges faced by young scientists are enormous. Thesechallenges can start right before choosing a graduate school orlaboratories to find a better career after post-graduation. In betweenthese challenges lies some biggest hurdles; proposing researchtheme, designing and conducting it, interpreting the results,accepting the failures and modifying the experiment and get yourresearch published. These are the gross challenges and are accom-panied by hundreds of problems to be solved on a daily basis. Thesefacts, although sounds depressing are exciting as well. The key toovercoming these obstacles is to better plan and understand theseissues right from the beginning and gradually master the skill.Weisman RG, in “Advice to young behavioural and cognitivescientists” suggests that the choice of experiment should come fromnature rather than beginning in a laboratory and hoping for anapplication in nature. To design an experiment, you need to have ahypothesis and is better if you have alternative hypothesis for anexperiment. A young scientist should always be ready to acceptfailures and criticism. Nobel laureate Medawar PB in his book“Advice to Young Scientist” states that “All experimentation iscriticism. If an experiment does not hold out the possibility ofcausing one to revise one's views, it is hard to see why it should bedone at all.” The other important factor to have a better career is“networking”. The innovative ideas most of the time comes fromdiscussion which can help you in modifying your research to anunimaginable direction. Having good communication with co-workers, peers, and supervisor makes research journey joyful. Theconferences and scientific meetings are the most important placeswhere one can have information regarding future career. Internetaccess and social networking sites have made the research worldsmall these days, and a young scientist should take advantage ofthese technologies. In my presentation, I will be sharing some of my

experiences and learned advice that I hope will be useful in makingthe journey of young scientists exciting.

doi:10.1016/j.cca.2019.03.1452


Worldwide YS groups/organizations. Different boarding models

C.E. ImperialiHospital de Viladecans, Spain

The training of young people to become specialists in LaboratoryMedicine must integrate, not only the accurate knowledge and skills,but also have to enhance the relationship between the community.Sharing experiences and inquisitiveness between young scientists(YS) is one of the key factors to ensure a future successful path inlaboratory medicine. The linkage between YS groups from differentnational or international societies is an essential point to promotesynergies and cooperation worldwide among them and boostlaboratory medicine. Different boarding models of YS groups andorganizations are coexisting worldwide. Some of them are integratedinto scientific societies. They are engaged in a variety of activities,even in some countries, congress just for YS are organised. Incontrast, some regions lack a well consolidated group. May be due tothe fact that Laboratory Medicine is an emerging specialization withits own character. The main goal of this talk is to help them known inorder to facilitate the interaction and the joint work.

Within the framework of YS session, having the benefit of theattendance of young people around the world, this talk will create agood opportunity to meet and share experiences for all of us.

doi:10.1016/j.cca.2019.03.1453

Symposium Wednesday 22 May 2019 - Hemoglobin A1c in clinicalpractice

Should HbA1c POCT be accepted for diagnosis of type 2 diabetes?

E. Lenters-Westraa,baClinical Chemistry Department, Isala, Zwolle, The NetherlandsbEuropean Reference Laboratory for Glycohemoglobin, Location Isala,Zwolle, The Netherlands

Point-of-care testing (POCT) is the fastest growing market inclinical chemistry. Today there are developments to transitiondiagnostics from the second line (in the hospital) to the first line(in the family physician's office) or even to the zero line (in thepatient's home). Assuring of the quality of the POCT instrument usedis crucial and should be embedded in a chain of quality control,otherwise the impact on patients will be immense, especially if thesemethods will be used for the diagnosis of different diseases.

POCT ensures the rapid provision of diagnostic information,ideally during one consultation, enabling clinical decisions to bemade at the earliest opportunity. Such rapid provision of informationmay facilitate optimization of the care process. The potential for anyapplication of POCT can, therefore, be judged in terms of its


contribution to decision making and to the process of care. In thecase of the management of diabetes patients, HbA1c POCT may offera number of advantages as long as the performance characteristics ofthe analyzers used are equivalent to those employed in the centrallaboratory and are certified as such. Most of the HbA1c POCTinstruments on the market are certified by the National Glyc-ohemoglobin Standardization Program (NGSP) but unfortunatelyusers of POCT are not always obliged to participate in externalquality assessments and therefore we do not really know what theanalytical performance is in daily routine and in the hands of endusers.

A few years ago HbA1c has been advocated as a diagnostic markerfor diabetes as a result of global standardization of the HbA1c assayand major improvements in analytical performance of differentHbA1c methods made by the manufacturers. But how good shouldan HbA1c method be? What is the impact of precision and bias onclinical practise? Should we make a distinction between HbA1claboratory based methods and HbA1c POCT methods for thediagnosis of type 2 diabetes?

In our reference laboratory the analytical performance of differentHbA1c methods, POCT and laboratory based methods, was investi-gated using certified protocols. In this presentation, I will use theresults of some of our evaluation studies to try to find an answer onthese questions.

doi:10.1016/j.cca.2019.03.1454


External quality assessment of HbA1c; Lessons learnt and futureprospects for quality targets

C. WeykampIFCC Network Coordinator, Laboratory, Queen Beatrix Hospital,Winterswijk, The Netherlands

In consecutive working groups and committees, the IFCC hashad a long standing interest in HbA1c. After having established areference measurement procedure and network of referencelaboratories, the focus moved to monitoring the success ofstandardization. The first step was the development of a modelfor quality targets with criteria that can be used at the level ofindividual laboratories but also to evaluate the performance ofcountries and manufacturers. A large scale application is theEurA1c trial: once a year external quality assessment organizersof a number of countries use the same samples and share data toget an international overview of the performance of HbA1c. Thefirst trial was organised in 2016 and covered 2166 laboratories in17 countries. The mean bias was 0.2 mmol/mol (0.02% in NGSPunits) with a between laboratory CV of 4.4% (3.0% NGSP units). Interms of the IFCC model, 55% of the countries and 58% of themanufacturers passed the criteria. Substantial differences wereseen between both countries and manufacturers. In the 2017, trial2647 laboratories participated and results improved slightly. Theresults of the 2018 trial with participation of 4000 laboratories arenot yet evaluated at the moment that this abstract was writtenbut will be presented in the lecture. Comparison with previoustrials will disclose trends. In addition, the criteria of the IFCCmodel for quality targets will be discussed in relation to qualityrequirements for use of HbA1c in monitoring, screening anddiagnosis of diabetes.

doi:10.1016/j.cca.2019.03.1455


Defining remission of diabetes after bariatric surgery

C. Le RouxChemical Pathology, University College Dublin, Ireland

Type 2 diabetes is considered a chronic and progressive disease.Despite the mission statement of the American Diabetes Association(ADA) for many years of aiming to cure diabetes, they didn't have adefinition for “cure” until 2009. Bariatric surgery precipitated thisrething, but even though surgery was predominantly used for thetreatment of obesity, in 1995 Walter Pories published a paper withthe provocative title: “Who would have thought it? An operationproves to be the most effective therapy for adult-onset diabetesmellitus”. The observation was made that patients with type 2diabetes developed normoglycaemia within days after bariatricsurgery. It took more than a decade for this observation to beacknowledged by the diabetes community, but in 2009 the ADAestablished a working group who defined cure of type 2 diabetesbecause of the mounting evidence after bariatric surgery suggestingthat type 2 diabetes could be placed into remission. The consensuswere that Partial remission should be defined as 1. hyperglycemiabelow diagnostic thresholds for diabetes, 2. at least 1 year's durationand 3. no active pharmacologic therapy or ongoing procedures.Complete remission was defined as 1. normal glycemic measures, 2.at least 1 year's duration and 3. no active pharmacologic therapy orongoing procedures. Cure or prolonged remission was defined as 1.complete remission of at least 5 years' duration.

Clinicians in the field have struggled to agree which of thesedefinitions are most appropriate and the 12 randomized controlledtrials comparing best medical care with bariatric surgery have usedvery different criteria for their endpoints. This talk will review theadvantages and disadvantages of using the various diagnostic cut-offs to define remission of diabetes and what the clinical implicationsmay be.

doi:10.1016/j.cca.2019.03.1456

Symposium Wednesday 22 May 2019 - Laboratory medicinetraining in Europe

Practical knowledge and skills management- Why to participate?

E. HomsakDepartment for Laboratory Diagnostics, University Clinical CentreMaribor, Maribor, Slovenia

In many EFLM Member Societies, there is a need to acquireadditional practical knowledge and skills in different fields ofLaboratory Medicine (LM), which may be obtained in otherlaboratories in the country or abroad. Until now, there were nopossibilities, on an official and open way to find the link to suchadditional but very important education, especially for youngtrainees, but also for all other European Specialists of LaboratoryMedicine (EuSpLM), who want to share the knowledge of LM on a


different level. Under the umbrella of EFLM, as a main and centralEuropean professional organization, there is now an option whichcould help to address this problem: the project “Exchange ofpractical knowledge and skills in Laboratory Medicine” which theWorking Group for Congresses & Postgraduate Education (WG-CPE)is developing.

The aim of this EFLM project is to create and operate a network ofmedical laboratories willing and able to offer practical training invariousfields/aspects of LM. Training opportunities in the database canrange from visiting, general specialist training to gain skills necessaryfor specialized measurement methods or systems, introductionspecific field of diagnostics and research work. A dedicated websiteEFLMLabX programwas developedwithin the frame of themain EFLMwebsite, offering the possibility to search and apply to the above-mentioned offer and to establish direct links and communicationsbetween both, providers and users /applicants of practices.

With such a project we will be able on EFLM level to achieve ahigher level of experience on different diagnostic methods, fields ofLM, to share the knowledge and experience among practice indifferent lab-institutions, to offer the opportunity for the youngtrainees and specialist to expanding contacts.

To support and stimulate this important exchange of knowledgeand skills in LM, especially for young trainees, we would like to createthe foundation for Bursaries, that will be supported by IVD partners.

With this project, according to the obtained a higher level ofknowledge/experience on the different field of laboratory diagnosticsof the general professional population(of EuSpLM), better networksbetween professionals, experts and scientists we will gain highergeneral quality of our profession.

doi:10.1016/j.cca.2019.03.1457


Research opportunities & skills - Gateway for careerenhancement

P.K. DablaGB, Pant Institute of Postgraduate Medical Education & Research(GIPMER), GNCTD, Delhi, India

Research is an academic activity. The purpose of research is todiscover answers to questions through the application of scientificprocedures to find out the truth which is hidden and which has notbeen discovered as yet. Research nearly provides the basis for nearlyall government policies in our economic system. Most clinicalresearch scientist positions require either an advanced degree inthe biological sciences or a medical degree. Some universities alsooffer master's degree programs in clinical research and learningabout research procedures, scholarly publication practices, biostatis-tics, professional ethics and clinical trial practices. Many clinicalresearch scientists choose to complete a dual degree program withmajors in medicine and science which offers learning about medicalpractices and advanced research methodology. Clinical researchscientists may work at universities, hospitals, pharmaceuticalcompanies or for the government setup with the goal of under-standing the causes of diseases, develop vaccines or medicines fortreatment, clinical trial drugs and therapies. As the healthcare israpidly growing both in knowledge and technology, so it is essentialfor young scientists and budding researchers to update the

knowledge through different means of continuous education suchas conferences, webinars, online courses etc. It will be advantageousand help them to attain high-level professional & managerialpositions within their respective medical facilities.

doi:10.1016/j.cca.2019.03.1458


European young scientists: Training and career

G. BoursierIFCC Task Force for Young Scientists, CHU Montpellier, Univ Montpellier,Department of Medical Genetics, Rare Diseases and PersonalizedMedicine, Rare and Autoinflammatory Diseases Unit, Montpellier, France

International Federation of Clinical Chemistry (IFCC) Task Forcefor Young Scientists (TF-YS) is a group which aims to fulfill the needsof young scientists. For the purposes of definition, a young scientist isa medical, pharmaceutical or science graduate working or training inlaboratory medicine and aged b40 years.

An objective of the TF-YS is to link young scientist initiatives withnational society and to encourage young scientists to shareexperience of laboratory medicine around the world. In this lines,the TF-YS recently conducted a survey about young scientiststraining worldwide. A questionnaire was addressed to all youngscientists in lab medicine through IFCC TF-YS contacts and socialmedia. Answers were collected online from July 2018 to November2018. The survey was dealing with areas of expertise, degrees,training, everyday practice and perspectives.

We received 243 answers from 57 countries. At this presentation,we will focus on the 96 respondents from the 20 European countries.Median age of the respondents were 32 years old (from 19 to 40years old). Nearly 80% sign and interpret results for patients in youreveryday practice and 46% do research (mainly clinical) N50% of thetime. To conclude this symposium, we will try to draw the portrait ofEuropean young scientists in the idea that it will facilitateopportunities for young scientists to participate in national andinternational exchange programs.

doi:10.1016/j.cca.2019.03.1459

Symposium Wednesday 22 May 2019 - External quality assurancein the digital era

Can patient medians replace or give additional value to thetraditional external quality assessment schemes?

L.M.R. Thienpont1

Ghent University, Belgium1Current affiliation: Thienpont & StöcklWissenschaftliches Consulting GbR, Germany.

External quality assessment (EQA) is an essential part of qualityassurance in laboratory medicine. To cover the spectrum of sources


potentially invalidating the analytical process “EQA according toobjective” is required. The main objectives are (i) participant and (ii)method assessment. Each allows a dedicated design: for (i) thedesign can be based on lyophilized samples and peer group targetsetting, while for (ii) a design with commutable samples and singletarget assignment is paramount. EQA schemes are provided nation-ally or regionally, but we believe it is time for improvement. Indeed,most of the current EQA programs have limitations, e.g., retrospec-tive reporting prohibiting timely remediation of analytical issues;lack of demonstrating factors influencing the performance (e.g., lot-to-lot variation); mixing up of design elements (e.g., methodassessment with potentially non-commutable samples); qualityspecifications which do not necessarily reflect that passing in EQAalso means correct medical decision. Based on experience from apilot study, we propose a complementary low-cost cornerstone toEQA. It is web-based, internationally run and utilizes a database builtfrom patient results (thus without commutability issues). To giveinput, laboratories only need an IT-solution (mostly already availablein modern Laboratory Information Systems) allowing stratification ofresults from outpatients, calculation of instrument-specific dailymedians and % flagging, and automatic electronic transmission of thecomputations. Via a user interface laboratories can consult graphsvisualizing the course of their moving medians reflected againststability limits. Also overviews of peer group results in box- andwhisker plots are provided. By way of examples we will show thatthe proposed “sample-less” EQA indeed overcomes limitations oftraditional programs and adds value, e.g., by allowing continuousmonitoring of short- to mid-term stability of performance (inclusiveeffects of influencing factors) and impact of analytical variation onthe flagging rate. This combination may serve as a fresh look onrealistic quality specifications. The database further can reflect on thecomparability among test systems and laboratories and be anincentive for harmonization.

doi:10.1016/j.cca.2019.03.1460


Present and future possibilities of virtual EQA

I. JuhosUniversity of Szeged, Hungary

Virtual external quality assessment (EQA) uses digital technologyonly in the EQA process. Certain EQA surveys can be supported thisway, which does not require real sample material e.g. those whichdeal with expertise of lab users or operation of labs. In the talk, somewidely used use cases of virtual EQA will be presented from thecurrent practice such as virtual microscopy or pre/post-analyticalsurveys, furthermore some future possibilities will be shown forinstance using mobile apps, improving artificial intelligence algo-rithms by EQA data, analysing routine data of labs besides EQA dataor organising large scale international surveys.

doi:10.1016/j.cca.2019.03.1461


Challenges in EQA and POCT

A. StavelinNoklus, Haraldsplass Diaconess Hospital, Bergen, Norway

With the expanding use of point-of-care testing (POCT) world-wide, it is important to have a good quality management system toensure that the measurement quality is satisfactory. The qualitymanagement system should include internal quality control andexternal quality assessment (EQA), but also training, education andguidance. Guidelines recommend that POCT users should participatein an EQA scheme whenever available. It is however, challenging forthe EQA organizers to provide such schemes because of the largenumbers of control samples needed, the possible requirement ofdifferent control materials for different POCT instruments, and thelack of tradition for quality control systems in these locations.

A key issue in EQA is to ensure high quality schemes and to avoidthat participation in such schemes does more harm than good. TheEQA providers should strive to obtain and use native commutablematerials, however, in many cases this is not possible. Such materialshave severe limitations since the material may also not becommutable between reagent lots within the same method.Circulation of unsuitable EQA materials could in such cases generateharm by misclassifying participant performance.

For POCT it is even more difficult to obtain commutable controlmaterials since the matrix generally is whole blood. Often differentcontrol materials must be circulated to the different POCT instru-ments, and infact no materials are available for some instruments. Analternative EQA approach has been developed in situations wherecommutable control materials are not available, in which a limitednumber of selected general practitioner offices perform a splitsample comparison with a central laboratory method using nativewhole blood patient samples. In addition, non-commutable EQAmaterials are circulated to all participants. In this way, methodperformance is addressed by the split samples system and partici-pant performance is addressed by the non-commutable material, andthe EQA provider does not need to circulate native materials to allthe participants.

Noklus has N25 years' experience with quality assurance of POCTin Norway. It has been shown that participating in this qualitysystem over time can improve the POCT performance.

doi:10.1016/j.cca.2019.03.1462

Symposium Wednesday 22 May 2019 - Preparing the professionfor compliance with the new IVD Regulation 2017/746 in Europe

The new IVD regulation 2017/746 and consequences for labora-tory medicine

C. CobbaertLeiden University Medical Centre, Leiden, The Netherlands

In Europe the “stringent” In Vitro Diagnostic Medical DeviceRegulation (IVDR 2017/746) comes into effect on 26 May 2022 andwill replace the “soft” IVD Directive (IVDD 98/79/EC). The rationale


for the IVDR is related to the fact that the European Commissionaims to create a single market for IVD tests in the EU and to improvetest safety and performance. The new IVDR will have majorconsequences for the IVD-industry and medical lab professionals,due to additional requirements for EU legislation to affix a CE markon their products and tests. The major changes in the new IVDR willbe highlighted so that attendees and stakeholders are enabled torecognize the challenges ahead.

We are now in the middle of the transition period as the IVDR willbecome fully effective onMay 26th 2022. The European Commission iscurrently preparing the interpretation of the regulation as well as thecritical infrastructure for its implementation. The “race-against-the-clock” has started as industry's ability to keep medical tests on themarket beyond theMay 26th 2022 deadline can only be accomplishedin case of timely delivery of the infrastructural components. If progressis too slow, the IVDR could seriously hamper the continuity ofdiagnostic testing and patient care. Other challenges are the newclinical evidence requirements in the IVDR which should be guidedand set by experts -such as methodologists and epidemiologists- in arational way in order not to jeopardize timely introduction of bettertests for improved patient care. Finally, lab professionals shouldprepare themselves by overseeing the impact of the new IVDR on e.g.test menu's (CE-IVDs and LDTs) and Test Evaluation. To that end, a fit-gap analysis should be executed in each medical lab in order toinventorize the LDTs, to document their justification and clinicalevidence, and to explore their compliance with the IVDR.

Referenceshttps://eur-lex.europa.eu/legal-ontent/EN/TXT/PDF/?

uri=CELEX:32017R0746&from=EN

doi:10.1016/j.cca.2019.03.1463


Defining clinical performance specifications in the new IVD era

S.J. LordThe EFLM Working Group on Test Evaluation

New IVD regulations require evidence of the clinical performanceof the device for intended use. This session presents a practical guidefor setting minimum clinical performance specifications for a newmedical test that researchers can use when developing a performanceevaluation plan for a new assay to meet regulatory requirements.

Clinical performance specifications are a set of criteria thatquantify the clinical performance a new test must attain to allowbetter health outcomes than current practice for the same indication.To set these levels, one must define the intended benefits for patientsof true positive and negative results, and the potential harms of falsepositive and negative results, relative to current practice without thenew test. We classify the intended benefits of a test into threecategories and provide examples to describe how to set minimumclinical performance levels for each category using a clinicaldecision-making framework.

Using this approach, a study that demonstrates clinical perfor-mance above the specified minimum acceptable level providesevidence that clinical performance is sufficient for intended use. Insome cases, this evidence will also be sufficient for conclusions aboutimproved health outcomes. For other cases where uncertainty exists

about health outcomes, clinical trials will still be needed to providedefinitive evidence that the benefits of testing outweigh the harms.

doi:10.1016/j.cca.2019.03.1464


What type of clinical evidence study designs are required in thenew IVDR era?

P. Bossuyt Eflm Working Group Test Evaluation

Amsterdam University Medical Centers

The new IVD regulations were approved by the EuropeanParliament in 2017, and will be fully applied from May 26, 2022,onwards. This In Vitro Diagnostic Regulation (IVDR) supersedes anolder Directive 98/79/EC.

One of the more significant changes introduced in the IVDR is therequirement for generating clinical evidence. This will apply to manymore IVD, compared to the previous situation. The need to collectclinical evidence will be proportionate to the risk class.

In general, clinical evidence is needed to demonstrate that thedevice is fit for purpose and achieves the intended performance,based on the intended use. This applies both to novel tests andexisting IVD. The IVDR makes a distinction between scientificvalidity data, analytical performance data and clinical performancedata.

It is still not very clear how this will work out. The evaluation ofmedical tests is challenging, because of the indirect link betweentesting and patient-important outcomes. In most cases, tests resultsare used to guide clinical actions, and the downstream actions andtheir consequences will eventually affect patients and citizens.

Though the IVDR does not require manufacturers to demonstrateeffectiveness (an improvement in outcomes) or cost-effectiveness (a(more) efficient use of resources), it will be challenging to collectenough data to show that the IVD is fit for purpose. We will for suresee more IVD trials.

In this presentation we will highlight how the key terms in theIVDR are connected, and we will briefly discuss the study designsthat generate the evidence required. We will do so using real andhypothetical examples.

doi:10.1016/j.cca.2019.03.1465


A comprehensive framework for test evaluation under the newIVD regulation

A. HorvathNew South Wales Health Pathology Department of Clinical Chemistry &Endocrinology, Prince of Wales Hospital, Sydney, Australia

In addition to Directive 98/79/EC, which required the demonstra-tion of the analytical performance characteristics of a test, the new InVitro Diagnostic (IVD) Regulation 2017/746 also requires clinical


evidence to demonstrate that the device is fit for purpose for theintended clinical application.

The EFLM Working Group on Test Evaluation has developed acomprehensive framework to aid researchers, laboratory scientistsand the IVD industry when laboratory tests are developed and testedfor analytical and clinical performance, clinical utility and otherrelevant impacts on patient care and health outcomes.

This presentation defines the key terms, principles and compo-nents of the test evaluation process and describes the pathway ofhow a laboratory assay measuring a biomarker fulfils an unmetclinical need and becomes a medically useful test. We illustrate withsome examples the importance of defining clinical goals and how theintended application of the biomarker in the clinical pathway drivesa dynamic interplay between the various components of the cyclicaltest evaluation cycle.

doi:10.1016/j.cca.2019.03.1466

SEQC Symposium Wednesday 22 May 2019 - Personalizedimmunosuppression to improve clinical outcomes

Pharmacogenetic biomarkers predictive of the pharmacokineticsand pharmacodynamics of immunosuppressive drugs

T. Van GelderDepartment Internal Medicine and Pharmacy, Erasmus Medical Center,Rotterdam, The Netherlands

In the literature there are many published papers on thecorrelation between polymorphisms in genes encoding for metabo-lizing enzymes and drug transporters, and pharmacokinetic data onimmunosuppressive drugs. Many of them refer to retrospectivestudies, and typically lack clinical outcome data. Despite the fact thata substantial proportion of these papers show significant associa-tions, in daily practice the implementation of pharmacogenetic testsis still very limited.

One of the reasons for the limited implementation is the currentlack of evidence of improved clinical outcome with pharmacogenetictesting. Furthermore, with efficient therapeutic drug monitoring it ispossible to rapidly correct for the effect of genotypic deviations onpharmacokinetics, thereby decreasing the utility of genotype-baseddosing. The future of pharmacogenetics will be in treatment modelsin which patient characteristics are combined with data onpolymorphisms in multiple genes.

These models should also focus more on pharmacodynamicparameters, variations in the expression of drug transporter proteins,and predictors of toxicity. These aspects have been under-studied sofar. PK/PD models will provide more information than the relativelysmall candidate gene studies performed so far. Furthermore, largerconsortia such as The International Genetics & Translational Researchin Transplantation Network (iGeneTRAiN) will be able to deliver newinsights into the genetic architecture of transplant-related outcomesacross a range of different solid-organ transplants.

For implementation of these models into clinical practice, linkageof genotype data to medication prescription systems within elec-tronic health records will be crucial.

doi:10.1016/j.cca.2019.03.1467


Improving clinical outcome using TDM in paediatric livertransplantation

E. FraucaServicio Hepatología Infantil y Trasplante Hepático, HospitalUniversitario La Paz, Madrid, Spain

Liver transplantation currently represents a consolidated treat-ment option for some of the liver diseases, acute or chronic, inchildren. Since its implementation in the late eighties we have seencontinuous improvement in its results up to a current situation inwhich the majority (90%) of patients survive long term after theprocedure and in most cases maintaining a normal graft function. Asis logical, this improvement cannot be attributed to a single reasonbut to the convergence of multiple advances in both the surgical andmedical levels. Within this last section is considered essential thecurrent availability of more effective and safe immunosuppressivedrugs and the accumulated experience in its management.

Since they are drugs with a narrow therapeutic index ensure theireffectiveness and safety mostly rely in the continuous monitoring oftheir blood levels. In the case of the paediatric patient, thismonitoring is particularly important given their high life expectancyafter the transplant with prolonged exposure to this pharmacologicalimmunosuppression situation and the risks derived from it.

In the medium or long term, the most frequent post-transplantcomplications depend more on the toxicity or side effects of thedrugs than on their lack of efficacy in the prevention of rejection. Therate of acute cellular rejection has been reduced to 15–20%, and inmost cases will be resolved with the increase in immunosuppressionwhile chronic rejection is very rare (around 5%) but in most cases itwill condition the loss of the graft and the need for retransplantation.

The management of renal toxicity, the susceptibility to certaininfections such as CMV or Epstein Barr virus and its consequences,such as lymphoproliferative disease, or the lack of adherence toimmunosuppressive treatment are some of the potentially seriouscomplications that can be prevented and managed with an adequatemonitoring of the immunosuppressive treatment.

Finally, in the last few years it has been demonstrated throughroutine biopsies, even in patients with normal graft function, thedevelopment of inflammation and fibrosis lesions that, according tothe available evidence, would probably have an immunological basis.This reality represents the need and challenge of improvingimmunological monitoring over the current available to ensure thelong-term survival of patients and grafts.

doi:10.1016/j.cca.2019.03.1468


Monitoring tacrolimus intracellular concentrations: Would ithelp better predicting graft clinical outcome?

F. LemaitreRennes University Hospital, France

Therapeutic drug monitoring (TDM) of immunosuppressive drugs(ISD) (that is the measurement of whole blood concentrations of ISD


allowing adjustment of ISD dosage) has revolutionized the manage-ment of solid organ transplant recipients. Hence, TDM of ISDparticipated decreasing the rate of graft rejections due to lowexposure to the immunosuppressive therapy, limiting, then, graftimmune lesions, graft loss and ultimately patients' death. Moreover,as ISD and particularly calcineurin inhibitors (tacrolimus andcyclosporine), display an obvious concentration-toxicity relationship,TDM also allows decreasing drugs' adverse events such as nephro-toxicity. However, in recent years and despite intensive TDM, graftrejection rate is no longer decreasing meaning that newer ways forISD monitoring are needed. Among those new approaches, measur-ing intracellular ISD concentrations appears as a promising approach.Indeed, some patients exhibit graft rejections or adverse eventswhile having whole blood concentrations within the therapeuticrange. These observations suggest that whole blood concentrationsare not completely related to the pharmacological drug effect.Measuring ISD concentrations inside its site of action (i.e thelymphocyte) might, therefore, be of better relevance than measuringdrug in whole blood. Intracellular concentrations might also be abetter surrogate of unbound drug concentrations that is the fractionavailable to exert the pharmacological effect of the drug. Most of thestudies on that topic have been conducted on tacrolimus, which isthe gold standard of actual immunosuppressive therapeutic regi-mens, probably because of its ability to interact with membranetransporters potentially influencing drug disposition into the intra-cellular compartment. The aim of this presentation is, then, to reviewthe current evidences of the interest of intracellular TDM oftacrolimus as a tool aiming at helping better predicting clinicaloutcomes in various type of solid organ transplantations.

doi:10.1016/j.cca.2019.03.1469


The role of biomarkers in solid organ transplantation

M. BrunetPharmacology & Toxicology, Biochemistry &Molecular Genetics, Bio-medical Diagnostic Center, University of Barcelona, Hospital Clinic ofBarcelona, Spain

Advances in immunosuppressive therapies and therapeutic drugmonitoring (TDM) have notably improved short-term transplantoutcomes. However, transplant recipients still exhibit much highermorbidity and mortality than the general population, one of themain causes being the co-morbidities influenced by the use ofchronic immunosuppressive drugs (ISDs).

In response to these clinical needs, in the last decade manychanges regarding the clinical management and TDM of ISDs havebeen introduced with the aim to minimize the adverse effects ofthese drugs and improve their effectiveness. Several studies haveevaluated new therapeutic ranges for tacrolimus, lower than those ofthe previous decade, based on post-transplant time, concomitantimmunosuppressive medication and the patient's immunologicalrisk. In addition, considering that similar concentrations of tacroli-mus produce different degrees of immunosuppression in treatedpatients, several groups have focused on evaluating the clinicalusefulness of pharmacodynamic and immunological biomarkerspredictive of the risk of rejection and graft clinical outcome.

Pharmacodynamic biomarkers monitoring by direct measurementof immunomodulatory drug-effect, combined with pharmacokinetics,has the potential to reflect a personalized response. In addition,monitoring non-invasive immunologic biomarkers could lead to furtherprognostic and diagnostic information regarding the risk of rejectionand allograft outcome at earlier time points and, thus allow therapy tobeadjusted toprevent severe graft injury. Considering the complexityofthese physiological processes, monitoring a short battery of biomarkersseems better than a single biomarker to personalize immunosuppres-sion and improve efficacy and safety profile.

The most representative results of the studies carried out in thelast decade on pharmacodynamic and immunological biomarkers arediscussed in this lecture. Grading of recommendations for themonitoring of some of these biomarkers is provided consideringtheir role in the selection of initial immunosuppression, targetconcentrations to be achieved, identification of good candidates tominimize immunosuppression, as well as in the improvement ofclinical outcome and long-term graft survival.

doi:10.1016/j.cca.2019.03.1470

Viewpoint Wednesday 22 May 2019 - Instrument verification:Time well spent?

Instrument verification - Time well spent

C. SturgeonRoyal Infirmary of Edinburgh, UK

Diagnostic manufacturers must provide relevant regulatorybodies with documented evidence that instruments meet perfor-mance specifications that fulfill the needs of their customers.Analytical requirements include excellent precision, reproducibility,repeatability, specificity and robustness to clinically relevant inter-ference. Data on clinical sensitivity and specificity, reference intervalsand interpretation are also required as part of the validationundertaken by the manufacturer.

In contrast, verifying that the same specified performancecharacteristics are maintained when a new instrument is introducedis a laboratory responsibility, as outlined in ISO 15189, and isessential for patient safety. Practical recommendations on minimumrequirements for verification of analytical performance are availablein a UK Association for Clinical Biochemistry and LaboratoryMedicine (ACB) and Nordic Association for Clinical Chemistry guide[www.acb.org.uk] which includes recently updated programs tofacilitate correct analysis of data generated.

Verification procedures provide initial assurance that an instru-ment is performing to specification in a routine laboratory setting,which is likely to be different from that of a highly qualitycontrolled manufacturer's laboratory. External quality assessmentscheme data repeatedly demonstrate within-method scatter ofresults that is likely to be due to differences in how laboratoriesuse and maintain their instruments or, less frequently, instrument-related differences.

Verification enables assessment of whether performance isoptimal. If not, reasons can be identified and addressed before anyclinical results are reported. Data generated during verification alsoprovide benchmarks against which future performance can beassessed, e.g. for possible deterioration. Bias comparisons with aprevious method using patient specimens provide helpful indicationof any clinical implications for interpretation.


Verifying the performance of a new instrument also providesopportunity to ensure internal quality control processes and rangesare appropriate, assess arrangements for data handling, estimaterequirements for consumables and offer interesting staff training.Well-planned and well-organised instrument verification is un-doubtedly time well spent.

doi:10.1016/j.cca.2019.03.1471

Viewpoint Wednesday 22 May 2019 - Instrument verification:Time well spent?

Instrument verification: Time well spent? No

E.S. KilpatrickDivision of Clinical Biochemistry, Sidra Medicine, Doha, Qatar

Instrument verification is performed by laboratory staff toensure any new testing meets the performance claims of themanufacturer prior to the analysis of patient samples. The currentprocess of verifying the measuring system of a laboratoryinstrument can be both time consuming and resource intensive,but the clear evidence that it is beneficial – never mind necessary- is lacking.

Even if this evidence existed, there are still inconsistenciesbetween professional organizations in the recommended elementsof verification required for a particular test (such as bias, impreci-sion, linearity etc) or how they should be assessed. Furthermore,there remains little consensus in the acceptance criteria that shouldbe applied, especially if this has not been clearly provided by themanufacturer. Added to this, the approach to verification oflaboratory instrumentation can be markedly different to that ofPoint of Care, even if the same analyte is being tested, inferring thateither too much or too little emphasis on verification is being placedon one of these measuring systems.

Lastly, the verification process itself can only be meaningful iffailed elements lead to an intervention aimed at improving testperformance. However, recent survey evidence would suggest thatthe most common response to not meeting acceptance criteria is tosimply accept the deviation.

doi:10.1016/j.cca.2019.03.1472

Viewpoint Wednesday 22 May 2019 - Data security: A laboratoryperspective

Data security: A pragmatic approach beyond the myths and hypes

J. RosslerCliniques Universitaires Saint-Luc, Belgium

In our current world where cyber-attacks stories hit the headlinenews every week, where GDPR is the new buzzword frightening allindustries and creating a business for consultancy companies, how toaddress data security from a laboratory perspective?

Without talking “bits & bytes”, we will review the issues we haveto tackle and suggest pragmatic approaches for this complex topic.Data security is often seen as an “IT-only” responsibility while theproblem's core is mainly to be found in processes and people.Investing in security software is needed but is only a small part of thesolution. What are the main attention points you should consider,which areas should you focus on, what is specific to the lab's world,how to cope with subcontracting, how to identify trusted partners?We will address those questions during the Viewpoint session.

doi:10.1016/j.cca.2019.03.1473

Symposium Thursday 23 May 2019 - Preanalytical phase – Stillchallenging for laboratory professionals

Serum indices: Simple and easy tool?

G. LippiSection of Clinical Biochemistry, University of Verona, Verona, Italy

On the assumption that quantification of cell-free hemoglobinremains the reference technique for identifying hemolyzed samplesand for rating the hemolysis degree, the in vitro diagnostic (IVD)companies have increasingly equipped their clinical chemistry, immu-nochemistry and hemostasis analyzers with automated methods forinterference evaluation. In particular, the manufacturers have devel-oped the so-called serum or plasma “HIL” (“Hemolysis”, “Icterus”,“Lipaemia”) indices, which enable automatic, rapid, accurate andvirtually inexpensive spectrophotometric assessment of hemoglobin,bilirubin and turbidity in the test sample. The underlying principleentails multiple spectrophotometric absorbance reading in diluted testsamples, thus including the wavelengths of peak absorbance of thethree interfering substances, followed by the use of algorithms andcorrection factors to resolve possible spectral overlaps. The mostimportant advantages are indeed represented by the high accuracy ofinterference quantification compared with the reference techniques(i.e., cyanmethemoglobin assay for hemoglobin assessment), the lowanalytical imprecision and insignificant impact on turnaround time.

Albeit the theoretical approach is similar, the companies havedeveloped different analytical approaches for quantifying thesepotential interfering substances. The leading divergences are repre-sented by different wavelengths and algorithms used for resolvingabsorbance into the interfering substance concentration, whichhighlights the very poor harmonization characterizing this methods.Some potential drawbacks have led to formulating some practicalrecommendations for improving clinical usefulness and harmoniza-tion of the automatic assessment of serum indices and H-index, thusincluding availability of precise information on how have beenidentified the analyte concentrations at which interference becomessignificant, the need of reporting data in a standardized measuringunit (preferably in g/L of hemoglobin), along with the opportunity toexpress results along a continuous (and not categorical) scale ofhemoglobin values. Importantly, transferability of the H-index valuesto the laboratory information system (LIS) is also highlyrecommended.

doi:10.1016/j.cca.2019.03.1474



Hemolysis: Detection and management

A. SimundicDepartment of Medical Laboratory Diagnostics, University Hospital SvetiDuh, Zagreb, Croatia

Hemolysis is the most common cause of sample rejection inmedical laboratories. Degree of hemolysis has long been and still isestimated visually in many laboratories worldwide. Visual inspectionof the degree of hemolysis is highly unreliable and it is thereforestrongly recommended that visual inspection is replaced withautomated detection systems. Although today considered to be astandard, there are several issues that make the everyday routine useof automated HIL indices still a challenge. Namely, automatedsystems for HIL detection differ respective to the measurementprocedure, reporting systems, definition of decision thresholds forsample rejection/acceptance, etc. European Federation of ClinicalChemistry and Laboratory Medicine (EFLM) Working Group for thePreanalytical Phase (WG-PRE) has therefore recently published a callfor more transparency in manufacturers declarations on serumindices. It is hoped that this as well as some future activities willpossibly lead to some improvement in this respect. Furthermore,both rejection or acceptance of hemolysed sample for analysis isassociated with potential risk for a patient. Whereas sample rejectionis associated with a need for sample re-collection and delay in resultsreporting, accepting hemolysed samples for testing may lead toreporting inaccurate results. Proper detection and management ofhemolysed samples is therefore of vital significance for patientsafety. A recent survey of EFLM WG-PRE performed on 37 Europeancountries (number of individual survey responses = 1405) hasdemonstrated that there is a huge variability between laboratoriesin the way they detect and manage hemolysed samples. Obviously,standardization and harmonization of this important preanalyticalsource of variability is necessary. EFLM WG-PRE has so far publishedseveral recommendations dealing with this topic. This lecture shallprovide an overview of the topic with a special focus on offeringadvice and guidance on the recommended ways to handle andmanage hemolysed samples in everyday routine.

doi:10.1016/j.cca.2019.03.1475


Stability studies: Room for improvement

M. CornesBiochemistry Department, Worcestershire Acute Hospitals NHS Trust,UK

Laboratory results are widely recognized as playing a key role inclinical decisions and the patient pathway. It is crucial therefore thatthe results that a laboratory produces both are both accurate andreproducible. Processes within the laboratory ensure that accuracyand precision is at a very high quality from the moment the samplereaches the laboratory but results can only be as good as the quality

of the sample received. Interest in the preanalytical phase has grownexponentially in recent decades and one aspect of this has beenlooking at analyte stability. It is important to know how an analytebehaves once outside of the body so that laboratory results areconsistent and accurately reflect the clinical picture and thereforeanswer the clinical question.

Currently there are no guidelines on how to report and performsample stability studies. There are however many studies anddatabases in existence that look at the stability of analytes. Many ofthese studies reproduce very similar studies previously performed onthe same analytes. The reason for this is that studies are often lackingdata, incomplete, contradictory and difficult to transfer betweendifferent healthcare settings. For this reason the European Federationof Clinical Chemistry and Laboratory Medicine Working Group forthe Preanalytical Phase has produced a set of documents to helpimprove the situation. The first phase of the project aimed toproduce a checklist against which future stability studies andmanuscripts should be based, similar to the STARD methodology.The checklist will serve as a guide to what should be considered andparticularly what information should be included in a publication tomaximise the transferability of the data between different healthcareenvironments. The second phase is to produce a set of criteria forevaluating stability studies that have been published to enable aquick, standardized way of determining the quality of the data andits applicability to different healthcare settings. It is hoped that thesetwo projects will ensure a future of more standardized andtransferable analyte stability studies and therefore data. Thepresentation will discuss the complexity of sample stability and gothrough the guidelines and checklists.

doi:10.1016/j.cca.2019.03.1476


To fast or not to fast: That is the question

J. CadamuroDepartment of Laboratory Medicine, Paracelsus Medical University,Salzburg, Austria

Laboratory values may be influenced by several controllable anduncontrollable preanalytical variables. One of the former is thefasting condition of the patient prior to blood collection. Food, water,alcohol and coffee intake as well as smoking potentially alterlaboratory test results. Although this circumstance may have asignificant impact on the interpretation of these results andsubsequently on further diagnostic workup and/or treatment,clinicians and nurses and especially patients are often not aware ofthis issue.

Current recommendations regarding definition and duration offasting differ quite substantially. Even with existing guidelines inplace, adherence to these is quite low throughout Europe. Addition-ally, some experts are discussing whether non-fasting values wouldreflect the patients current condition better than fasting samples.This, however, would demand new reference values for respectiveparameters, which in turn are dependent from the type and amountof food intake, among others.


Therefore, the European Federation of Clinical Chemistry andLaboratory Medicine (EFLM) Working Group “Preanalytical Phase”(WG-PRE) aimed to provide a framework for the harmonization ofdefinitions for fasting requirements, recommending to collect bloodfor all laboratory tests between 7 and 9 a.m. Fasting should last for12 h and alcohol should be avoided for 24 h before sampling. Coffeeand smoking should be refrained from on the morning of bloodcollection.

With this European recommendation, we now have a document,serving as basis for further standardization of the preanalytical phase.

doi:10.1016/j.cca.2019.03.1477

Symposium Thursday 23 May 2019 - Dyslipidemia guidelines inEurope and need for standardization of traditional and newcardiovascular disease biomarkers – Addressing cholesterol andbeyond

Update of dyslipidemia guidelines and the rationale of cardiovas-cular disease biomarker

M. LangloisDepartment of Laboratory Medicine, AZ St-Jan Bruges, BelgiumGhent University, Belgium

The multidisciplinary consensus panel of the European Athero-sclerosis Society (EAS) and the European Federation of ClinicalChemistry and Laboratory Medicine (EFLM) recently updatedrecommendations on the quantification of atherogenic lipoproteinsin nonfasting and fasting blood samples. The key recommendationsare: 1/ Fasting is not routinely required for the determination of alipid profile, but fasting should still be considered at high nonfastingtriglycerides concentration N 4.5 mmol/l (400 mg/dl). 2/ On-treat-ment follow-up of (measured or calculated) LDL-cholesterol concen-tration in a patient should ideally be performed with the samedocumented test method, to avoid inappropriate treatment decisionsdue to marked between-method/between-laboratory variability. 3/Lipoprotein(a) is included in (measured or calculated) LDL-choles-terol and should be assessed in patients not achieving LDL-cholesterol goals on statin treatment. 4/ Non-HDL-cholesterol (orapolipoprotein B) should be used as the secondary treatment targetin patients with mild-to-moderate hypertriglyceridemia, 2–10mmol/l (175–880 mg/dl), wherein LDL-cholesterol measurement orcalculation is less accurate and often less predictive of cardiovasculardisease risk. Non-HDL-cholesterol (= LDL + remnant cholesterolcombined) additionally includes the atherogenic risk component ofremnant lipoproteins and can be calculated as total- minus HDL-cholesterol in a standard nonfasting lipid panel. Apolipoprotein Bmore accurately reflects LDL particle number, often elevated inpatients with mild-to-moderate hypertriglyceridemia without nec-essarily having high LDL-cholesterol concentration. 5/ Laboratoriesshould automatically report non-HDL-cholesterol in all standard lipidpanels. 6/ Flagging of lipid profiles on laboratory reports should bebased on desirable concentrations (risk thresholds).

doi:10.1016/j.cca.2019.03.1478


Standardization of advanced lipoprotein testing: The BioSITraceproject

V. Delatoura, N. Clouet-Foraisona, N. Gaie-Levrelb, S. Marcovinac, A.Hoofnagled, Z. Kuklenyike, M. Caulfieldf, J. Otvosg, J. Contoisj, R.Kraussh, K. Kulkarnii, A. Remaleyk, H. Vespere, C. Cobbaertl, P. GillerymaLaboratoire National de Métrologie et d'Essais (LNE), Paris, FrancebLaboratoire National de Métrologie et d'Essais, Paris, FrancecNorthwest Lipid Metabolism and Diabetes Research Laboratories,University of Washington, Seattle, WA, USAdDepartment of Laboratory Medicine, University of Washington, Seattle,WA, USAeCenters for Disease Control and Prevention, Division of LaboratorySciences, Atlanta, GA, USAfQuest Diagnostics Nichols Institute, San Juan, Capistrano, CA, USAgLaboratory Corporation of America Holdings, Morrisville, NC, USAhChildren Hospital Oakland Research Institute, Oakland, CA, USAiVAP Diagnostics Laboratory Inc., Birmingham, AL, USAjSun Diagnostics, LLC, New Gloucester, ME, USAkLipoprotein Metabolism Section, National Heart, Lung, and BloodInstitute, Bethesda, MD, USAlDepartment of Clinical Chemistry and Laboratory Medicine, LeidenUniversity Medical Center, Leiden, The NetherlandsmUniversity Hospital of Reims, Laboratory of Biochemistry - Pharma-cology - Toxicology, Reims, France

Since the Framingham study on cardiovascular diseases (CVD),correlation between lipid disorders and increased CVD risk is wellestablished and evidenced the multifactorial origins of CVD. Evalu-ation of CVD Risk implies identifying the major risk factors (eg. age,gender, smoking or arterial hypertension) and measuring theconcentrations of circulating lipid markers such as total cholesterol,LDL-cholesterol (LDLc) and HDL-cholesterol (HDLc). However, aconsiderable number of patients with low risk profiles stillexperience cardiovascular events, even after reaching optimumcholesterol concentrations. Despite the usefulness of standard lipidparameters for CVD risk assessment, undiagnosed residual riskremains high. In an era of precision medicine, Advanced LipoproteinTesting (ALT) was developed to provide physicians with morepredictive diagnostic tools. However, results are sometimes conflict-ing and many believe there is insufficient evidence to support thewidespread use of these biomarkers in routine clinical practice. Sincedifferent ALT methods were involved in these studies, it wassuggested that the lack of agreement of clinical outcomes couldbe, in part, the result of a lack of agreement between analyticalmethods.

Objectives of the BioSITrace project were (1) to assess compara-bility of the major ALT methods available for the measurement ofapoB-100 and non-HDL-P concentrations and (2) to evaluate thepossibility of establishing a higher order reference measurementsystem consisting of a robust candidate reference method that wouldprovide SI-traceable results.

Through a split-sample study, 25 serum samples were assayed in10 laboratories using the major ALT methods for non-HDL-P or apoB-100 measurements (Immuno-nephelometry, LC-MS/MS, VAP, NMRand ES-DMA).


With a between-method RSD of 14.1%, it appears that thedifferent methods do not yet provide equivalent results for themeasurement of non-HDL-P and apoB-100. To improve measure-ment comparability, a preferred means consists in standardizingassay calibration through the establishment of a higher orderreference measurement procedure (RMP) and the production ofhigher order reference materials (RMs). LC/MS/MS appears as asuitable method for standardization of apoB and other apolipopro-teins. However, measurement of ApoA-I doesn't allow estimatingHDL-P because the number of ApoA-I molecules per HDL particle isnot constant. Also, apolipoprotein measurement doesn't allowestimating particle number concentration of sub-populations ofnon-HDL particles (eg. LDL-P, VLDL-P, IDL-P): other referencemethods are needed for these measurands.

doi:10.1016/j.cca.2019.03.1479


Standardization of tests in the ISO 15189:2012 era

P. GilleryLaboratory of Biochemistry-Pharmacology-Toxicology, University Hos-pital of Reims, Reims, France

Standardization of laboratory tests is a major part of the qualityprocess in laboratorymedicine, increasing the reliability of test resultsand their optimal clinical use. This topic constitutes a commonchallenge for many stakeholders including scientific societies, profes-sional organizations, manufacturers and metrology institutes.

Standardization efforts cannot be undertaken without referenceto the current scientific and regulatory contexts. Especially, the ISO15189:2012 standard is a milestone for quality assessment inlaboratories in many countries. This document specifies require-ments for quality and competences and may be used by medicallaboratories themselves for developing quality management systemand assessing their own competence, but also by external stake-holders for confirming or recognizing competence of medicallaboratories.

From a standardization perspective, various items apply withreference mainly to the traceability chain which ensures a controlledlink from the reference method to the delivery of patient test results.However, the demands of the 15,189 standard may sometimesconstitute puzzling challenges. This is especially true in the field oflipid metabolism for the establishment of guidelines used indiagnosis and monitoring of patients with cardiovascular (CV)diseases, regarding as well classical biological parameters and riskfactors as new measurands and biomarkers.

Indeed, “old” biomarkers (e.g. cholesterol) have benefited fromvalidated standardization procedures, and their values are used inclinical recommendations for evaluating CV risk and treatmentefficacy. However, it has been clearly evidenced that conventionalrisk factors do not detect all patients with CV risk. The search of newbiomarkers is then a major goal, especially in the field of lipoparticlesor apolipoproteins. However the complexity of these compoundsleads to complicated discussions regarding the definition of themeasurands and of the convenient reference methods. Suchconsiderations are taken into account both by the InternationalFederation of Clinical Chemistry and Laboratory Medicine for the

analytical aspects of standardization, and by the European Federationof Laboratory Medicine for establishing guidelines with clinicalscientific societies.

doi:10.1016/j.cca.2019.03.1480

Symposium Thursday 23 May 2019 - Performance specification inlaboratory medicine

Introduction

S. SandbergNoklus, Haraldsplass Deaconess Hospital, Bergen, Norway

How to set analytical performance specifications was discussed onthe 1th Strategic conference of EFLM in Milan 2014. Four models wererecommended:Model 1: Based on the effect of analytical performanceon clinical outcomes. Model 2. Based on components of biologicalvariation of themeasurand andModel 3. Based on state-of-the-art. It isrecommended that a list be made allocating measurands to differentmodels. Preference should be given to models 1 and 2. In somesituations, it can be advantageous to combine the different models.

After the Milan conference, four other TFGs were established: TFG1: To allocate different tests to different models for estimatingperformance specifications and to give an overview and a reason forwhy tests are allocated to the different models; TFG 2: To defineperformance specifications for the most common measurands thatshould be used by EQAS organizers; TFG 3: To come up with aproposal for how to use the total error concept and how to possiblecombine performance specifications for bias and imprecision; TFG 4:To come up with a general proposal on how to generate performancespecifications for the pre- and post-analytical phases and TFG 5 todevelop a critical appraisal check list for studies on biologicalvariation and to develop a new database with biological variationdata. All these task groups (TG) have fulfilled their Terms ofReferences and two new TGs have been established to take thework further: The TG- biological variation database (TG-BVD) andthe TG performance specification based on outcome studies whichwill be dealt with in the next presentations.

doi:10.1016/j.cca.2019.03.1481


Are biological variation data fit for purpose? Principles for thedevelopment of the EFLM biological variation database

A.K. AarsandHaukeland University Hospital, Bergen, Norway

The validity of analytical performance specifications and otherapplications based on biological variation (BV) data require that BVestimates are of high quality and relevant for the setting andpopulation to which they are applied. However, BV estimates for thesame measurand obtained from independent studies may varysubstantially. A compilation of published BV data for a large numberof measurands has been available in an online database, last updatedin 2014. Concern has been raised that some of these estimates may


not be appropriate for use today. With this background, the EFLMWorking Group on Biological Variation and the Task and FinishGroup for the Biological Variation Database developed the BiologicalVariation Data Critical Appraisal Checklist (BIVAC), published in2017. The BIVAC is designed to assess the quality of BV publications,focusing on effects of study design, the measurement procedure andstatistical handling of data on within-subject BV estimates. Based onindividual scores A, B, C or D for each of the 14 quality items, anoverall grade is given for the publication under review. Data fromstudies graded as A, B or C are used to populate the EFLM BiologicalVariation Database. As a first step, studies performed in healthyadults where sampling is weekly are used as basis for global BVestimates, delivered by a meta-analysis approach incorporating theBIVAC grade and the width of the confidence interval of the BVestimate. The EFLM Biological Variation Database aims at providingusers with evidence-based quality assured BV estimates for use intheir everyday laboratory practice.

doi:10.1016/j.cca.2019.03.1482


Individual ranges of biomarkers in the biological passport

P. SottasCoremedica, Campus Biotech, Geneva

The biological passport is an individual electronic document inwhich biomarkers of various sorts are collated over time. It hasapplications in all fields where a biological – not necessarily clinical –signal has to be detected. First applications have been in the field ofsport, for the enhanced detection of doping and of changes inperformance in all elite athletes through markers of doping and ofperformance, in the field of clinical trials for the enhanced detection of adrug effect with markers of efficacy and safety and indirectly thereduction of the number of patients to enrol to reach a given primaryendpoint, in the field of nutrition to enable personalized nutrition, andin the field of health such as for the early diagnosis of diseases. Giventhat up to 90% of biomarkers measured in biological fluids presenthigher between- than within-subject variations, key to the biologicalpassport is the definition of individual ranges of biomarkers. Anadaptive Bayesianmodel is used for that purpose. Thismodel is optimaltomove from population-based reference ranges – stratified or not – toindividual ranges of biomarkers. It has been shown that this modelgeneralises many models aiming to remove any between-factor sourceof variations, where the factor can be subject, day, laboratory, batch etc.This includes stratification according to heterogenous factors, effect ofgenetic polymorphisms on phenotypic biomarkers and the referencechange value model. With the rise of highly multiplexed assays andomics, recent developments of the biological passport include theapplication of AI-based unsupervised pattern recognition or supervisedclassification tools for the still enhanced detection of a biological signal.The biological passport is now available to anyone for any type ofbiomarkers and application through a secure electronic platform.

doi:10.1016/j.cca.2019.03.1483


How to establish analytical performance specifications based onclinical outcome studies – Practical examples

A. HorvathNew South Wales Health Pathology Department of Clinical Chemistry &Endocrinology, Prince of Wales Hospital, Sydney, Australia

In 2014 at its 1st strategic conference in Milan the EuropeanFederation of Clinical Chemistry and Laboratory Medicine (EFLM)proposed a new hierarchical model for defining analytical perfor-mance specifications (APS). The aim was to better answer “Howgood a test needs to be analytically to ensure that a test resultachieves clinical benefit without causing harm”. Model 1 sets theprinciples of outcome-based APS; Model 2 is based on components ofbiological variation; and Model 3 reflects the state of the art ofcurrent measurements.

One of the most challenging topics is to develop theoreticalmodels and practical tools for setting performance specificationsbased on outcome studies. Direct outcome studies investigating theeffect of analytical performance on health outcomes (Model 1a)would be ideal, but these types of trials are rare, complicated, costlyand often even unethical to conduct. Laboratory testing is oftenindirectly linked to health outcomes and the impact on patient well-being is much influenced by medical decisions when diagnosing/screening or monitoring patients and their compliance with andresponse to medical treatments. Therefore, the effect of testperformance on clinical outcomes is more commonly demonstratedby indirect studies (Model 1b) whereby the impact of analyticalperformance is investigated on disease classifications or on clinicalmanagement decisions. This indirect impact measurement is oftendone by simulation modeling or decision analysis.

After the Milan meeting the EFLM has set up a Task Group onAnalytical Performance Specifications based on Outcome Studies(TG-PSOS) to inform laboratories, IVD companies, QAP organizationsand guideline developers of the required APS for variousmeasurands. The work of this group is expected to set a benchmarkfor analytical quality of tests for various intended applications, andassist R&D and test harmonization processes, and compliance of theIVD industry with new regulatory requirements that demand clinicalevidence of test performance. In this presentation we describe thework of this group so far and present some tools and techniques forderiving APS from indirect outcome studies. We illustrate theseapproaches and the steps with examples of high-sensitivity Troponinand HbA1c testing.

doi:10.1016/j.cca.2019.03.1484

Symposium Thursday 23 May 2019 - Big data in laboratorymedicine

Qualitative and quantitative variety of big data

D. GrusonCliniques Universitaires Saint Luc, Belgium

The potential of health data to stimulate the development ofprecision medicine is tremendous. Data science will also provide a


new set of tools that improve the effectiveness of laboratorymedicine. Artificial intelligence (AI) is a field of computing sciencesand machine learning devoted to mimic human thought processesand behaviours. AI makes use of very different mathematical andalgorithmic approaches. In the field of healthcare, AI demonstratedsuccesses for image analysis in radiology, pathology, dermatologyand genomics analysis. AI has clearly the potential to generate a newrevolution and paradigm shift in laboratory medicine. Applications inlaboratory medicines will impact processes and care pathways, smarttests ordering, intelligent disease monitoring as well as personalizedtreatment and enrolment to clinical trials.

The potential of AI is also growing exponentially because of theflow, amount and variety of data available, constituting a real datadeluge. DNA (and many epigenetic modifications), RNA (in variousforms; messenger, long non-coding, or double strand), proteins,metabolome or microbiota can be measured, along with the moreand more structured clinical, medical and environmental data. Thesedata are however not always easily accessible due to several factors:the lack of standardization (different medical software productsused, structured vs. unstructured data, differences in syntax andterminology for describing similar observations), legal challenges(issues about privacy), financial limitations and ethical concerns thatstimulate revised regulation.

doi:10.1016/j.cca.2019.03.1485


Emerging technologies in the age of big data

L.J. KrickaDepartment of Pathology and Laboratory Medicine, University ofPennsylvania Medical Center, Philadelphia, PA, USA

Recent decades have seen the emergence of analytical methodsand devices capable of generating or collecting large amounts ofbiological information (“big data”). In parallel, has been thedevelopment and deployment of data analysis techniques capableof analysing large, complex data sets. High-resolution analyticalmethods that generate terabytes of information are now common-place (e.g., DNA sequencing), and new big data generating technol-ogies of differing complexity continue to emerge, e.g., a nuclearmagnetic resonance metabolomic method for blood analysis thattests for 220 biomarkers, and breath analysis using large nanomaterial-based sensor arrays. Continuous monitoring is anotherroute to acquiring large amounts of data. There are many “wear-ables”, part of the mobile health (mHealth) revolution, that can tracka range of health indicators (e.g., electrocardiogram, heart rate,activity), and prominent examples include the Apple iWatch, and theVerily Study Watch. These convenient, user-friendly devices arebeing used to collect data in large population studies (e.g., 10,000Parkinson patient study), and the camera on smartphones has beenexploited in a range of clinical tests including urinalysis, and skincancer detection. Medical imaging generates large amounts of dataand a particular focus has been the use of artificial intelligence (AI)and augmented reality to aid the analysis of medical images. RobustAI (deep learning) algorithms, developed to analyze 3-D opticalcoherence tomography images, can equal or exceed the accuracy ofhuman analysis. An augmented reality microscope uses machinelearning algorithms to analyze microscope images and select and

project areas to be examined into the field of view, thus acting as anintelligent assistant - aiding but not replacing the pathologist. Otherapplications of AI include genetic data analysis, telepresence, anddigital twins. Significant aspects of current developments areconcerns with medical device cybersecurity, and the expanding roleof companies new to healthcare technology (e.g., Apple, Amazon,Verily) that have interests in tools for medical data collection,storage and analysis, mobile health, and re-engineering healthcare.

doi:10.1016/j.cca.2019.03.1486


High-throughput technologies for gathering data

P. FortinaSidney Kimmel Cancer Center at Thomas Jefferson University, UnitedStates of America

Big Data is a very broad field and describes datasets with largevolume or complexity mainly leveraged to uncover hidden patterns,unknown associations and other insights. In laboratory medicine, bigdata is largely generated for genomic research and precisionmedicine. Genomic research attempts to build strategies fordiagnostic and therapeutic approaches to a specific disease byemploying next-generation sequencing technologies, such as wholegenome sequencing, whole exome sequencing, RNA sequencing,and/or targeted gene panel sequencing. Information obtained fromlarge scale NGS data is comprehensively combined with clinicalelectronic health records data to approach disease for individualizedtherapy, also referred to as precision medicine. While theseapproaches are improving our understanding of the diseases, theyrequire careful implementation of appropriate data analytics anddata handling methods since the volume of data generated by theseapproaches is astonishingly large. Therefore, to systematically store,manage, manipulate and mine this level of data systematicapproaches, suitable computing hardware infrastructure, nimblesoftware and new algorithmic approaches are of paramountimportance. This large-scale multi-dimensional data can be analyseddirectly for features including disease-causing mutations or pro-cesses, and/or complex analysis including integrated approaches ofdeep machine learning algorithms and artificial intelligence forbetter prediction and stratification of disease. Cloud computingservices such as Amazon Web Services (AWS) provides a niche forthis kind of multifaceted implementation by providing appropriatesecurity, storage, speed, and frameworks such as APACHE Hadoopand NOSQL database. Overall, the big data generated holds thepromise of supporting a wide range of medical and healthcarefunctions including disease prevention, therapy and clinical analytics.Data in life sciences and healthcare is expected to grow exponen-tially in the coming years and it is vitally important for academic,commercial and healthcare organizations to acquire the requiredtools and infrastructures to leverage the data effectively for insightfuldiagnosis, treatments and to result in a better quality patientoutcome.

doi:10.1016/j.cca.2019.03.1487



Value of big data: Data relevant to the health of individuals orpopulations

Z. Lub, K. SikarisaaMelbourne University, Parkville, Victoria, AustraliabMonash University, Clayton, Victoria, Australia

Increasing reliance on medical laboratory testing combined withautomation, amalgamation of laboratories have resulted in laborato-ries with huge databases of patient results. Community laboratoriespredominantly have the results of patients unaffected by diseasebecause their clinicians are often engaged in excluding disease,monitoring successful treatment and wellness testing. The use oflaboratory data to derive reference intervals is an indirect approachand often relies on statistical techniques to exclude disease affecteddata. This technique is especially useful in paediatrics, obstetrics andgeriatrics where direct methods are problematic in finding healthyvolunteers. Incorporation of clinical data of patients empowers notonly the accuracy of reference intervals by this direct method butalso helps to define clinical decision limits. It is very helpful whenclinical information is provided with the request form and recordedin the Laboratory Information System (LIS), however, the ultimatebig data environment is to have direct access to the electronic healthrecord. The correlation between laboratory results and clinicalinformation is not only useful in answering specific clinicalquestions, but also an important resource in knowledge discovery.Just as clinicians are expected to use their training and clinicalexperiences to optimise patient management, it can be argued thatlaboratories have an obligation to use their accumulated experience,stored as big data in their LIS, to optimise the role of laboratorymedicine in patient management. Laboratorians need to developskills in big data analyses and there is also a prerequisite that LISshould be designed to allow data access to laboratorians. While theremay be privacy and ethical concerns to consider when accessing bigdata from LIS, it has never been proposed that patient permission isrequired for laboratories to use running patient mean for qualityassurance, probably because (i) the data is effectively anonymousand (ii) the value of the patient mean may benefit both the patientsinvolved as well as many other patients. These principles of utilizingpatient information in quality assurance and improving clinicalmanagement generally apply to the use of big data in the medicallaboratory.

doi:10.1016/j.cca.2019.03.1488

SEQC Symposium Thursday 23 May 2019 - Chronic liver disease:The role of the clinical laboratory

Diagnosis and prognosis of patients with liver fibrosis based onclinical and laboratory parameters

M. PinzaniUniversity College London - Institute for Liver and Digestive Health,Royal Free Hospital, UK

Hepatic fibrosis, consequent to chronic liver diseases (CLD),previously assessed exclusively by liver histology, can now be

evaluated using “non-invasive” techniques. Non-invasive tests com-prise ‘serum markers’ (directly or indirectly related to fibrogenesis orfibrosis) and measurement of hepatic stiffness by elastography. Mostof the evidence base for the accuracy of these tests comes fromstudies of hepatitis C and Non Alcoholic Fatty Liver Disease. All non-invasive tests perform well in identifying the presence of cirrhosis(stage 4 fibrosis) but are less accurate and consistent in definingearlier stages of fibrosis.

It appears that Transient Elastography (TE), which measures liverstiffness, remains to date the most robust and widely used non-invasive test. Evolution of tissue elastography has led to the use ofultrasound devices capable of measuring tissue stiffness withdifferent physical modalities such Acoustic radiation Force Imaging(ARFI) or Shear Wave Elastography (SWE). These techniques allowan accurate localization of the point of interest and measurements indifferent zones of the liver during the same session. On the otherhand, they require a sufficient operator experience in ultrasoundmeasurements.

Non-invasive tests are proving of value beyond assessing thestage of hepatic fibrosis, including indicating Clinically SignificantPortal Hypertension, and a threshold has been proposed for decidingwhen and if endoscopy is done looking for varices. Splenicelastography and other more complex hepatic elastography tech-niques are under development and may become more widelyapplied clinically in the future.

doi:10.1016/j.cca.2019.03.1489


Chronic liver disease: The role of the clinical laboratory

M. Morales-RuizBiochemistry and Molecular Genetics Department, Hospital Clínic ofBarcelona, IDIBAPS, CIBERehd, Barcelona, SpainWorking Group for the Biochemical Assessment of Hepatic DiseaseSEQC-ML

Some areas of liver disease require a greater effort of laboratorytests implementation and interpretation. For example, early detec-tion of hepatocellular carcinoma, immunosuppressive therapy forliver transplantation, evaluation and staging of liver fibrosis,characterization of NAFLD to non-alcoholic steatohepatitis progres-sion and monitoring of HBV infection. Several laboratory tests arecurrently being used for these purposes. However, it is pertinent toconsider that pre-analytical and analytical factors may affect thediagnostic value provided by these tests. All these factors, in additionto intra- and inter-individual variations, are current challenges thatjustify a critical evaluation of the state-of-the-art for laboratory testsand the potential implementation of novel diagnostic and prognostictools. In this context, this topic symposium is intended to featurecompelling speakers sharing insight into these topics. The sympo-sium will provide a valuable opportunity for hepatologists andClinical Laboratory Professionals to share in common the present andfuture challenges in the management of chronic liver disease.

doi:10.1016/j.cca.2019.03.1490



Hepatitis B from the clinical laboratory: New markers for an olddisease

F. Rodriguez-FriasVall d'Hebron Clinical Laboratories (Vall d'Hebron Universitary Hospi-tal), Spain

250 million people are chronically infected with the hepatitis Bvirus (HBV), around 600,000 yearly death. HBV virions carry acircular not covalently closed and partially double strand DNA(rcDNA). The viral genome is stored as a “viral minichromosome”(covalently closed circular DNA: cccDNA) in the cell nucleus,remaining there till cell death. In addition, HBV genome can alsointegrate in the host genome. Interestingly, the viral cycle includes aretrotranscription step from an RNA transcript of this cccDNA.Antiviral treatment is mainly based in the inhibition of retro-transcription step, not affecting cccDNA transcription: (viral antigensproduction in spite of serum HBV-DNA undetectable). However,when stopping therapy, retrotranscription mostly reactivates, andinfection becomes active again. By this reason this infection iscurrently considered as uncurable. In addition to virions whichcontain rcDNA, other HBV particulate forms are present in theserum: a huge excess of subviral particles constituted just by viralenvelopes (HBsAg), virion-like particles which contains HBV RNA oreven virion-like particles without nucleic acid. Frequently the course

of chronic HBV infection is not clinically apparent and consequences(hepatic decompensation and development of hepatocellular carci-noma: HCC), usually occur only after decades (HBV is the main HCCcause all over the world). This fact is mainly due to that chronic HBVinfection is characterized by different phases, with varying conse-quences to the infected patients. In case of ongoing hepatitis,treatment is required to prevent disease complications. However,not all patients with chronic HBV infection will develop diseaseprogression. By this reason it is of utmost importance to identifypatients who are at risk and require antiviral treatment and/or closesurveillance. Clinical laboratories can apply the determination ofmultiple serum markers in order to achieve this: Viral antigens suchas Hepatitis B surface antigen (HBsAg) and Hepatitis “e” antigen(HBe). In addition, some specific antibodies such as against HepatitisCore Antigen (the viral capsid component) (Anti HBc total of IgM),against HBe (anti HBe) or against HBsAg (anti HBs, neutralizingantibodies). Moreover, some virological markers such as HBV-DNA,or viral genotype. Hepatic inflammation and quantification of HBVDNA have guided treatment decisions, which have been shown toreduce liver-related complications and death. Data on the quantifi-cation of additional HBV markers such as hepatitis B surface antigen(HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis Bvirus RNA (HBV RNA) have accumulated in recent years.

doi:10.1016/j.cca.2019.03.1491


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