The IFCC Curriculum - phase 1 Ronda F. Greaves, Janet M. Smith, Graham Beastall, Chris Florkowski, Loralie Langman, Joanna Sheldon, Elvar Theodorsson IFCC Committee for Distance Learning – for the IFCC eAcademy project

INFO IFCC CURRICULUM

Authors: THE IFCC CURRICULUM - PHASE 1 Ronda F. Greaves Janet M. Smith

Section Lead Authors: Graham Beastall Chris Florkowski Ronda F. Greaves Loralie Langman Joanna Sheldon Elvar Theodorsson

The IFCC Curriculum - Rev 0 December 2017 (effective until further revision)

Contact e-mail: [email protected]

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The IFCC Curriculum was developed as part of Mass Spectrometry Section the IFCC eAcademy project by the Committee Ronda F. Greaves for Distance Learning. School of Health and Biomedical Sciences - RMIT University AUTHORS: PO Box 71, Bundoora Janet M. Smith Victoria 3083, Australia [email protected] [email protected] Ronda F. Greaves Loralie Langman School of Health and Biomedical Sciences - RMIT University Department of Laboratory Medicine PO Box 71, Bundoora and Pathology, Mayo Clinic Victoria 3083, Australia 200 2nd Street SW, Rochester, MN 55905 [email protected] United States [email protected] SECTION LEAD AUTHORS: Research in Laboratory Medicine Section Evidence Based Laboratory Medicine Section Graham Beastall Chris Florkowski, on behalf of the IFCC Committee on Evidence-Based Laboratory Laboratory Medicine Consulting Medicine (C-EBLM) Mayfield, Birdston, Kirkintilloch Glasgow G66 1RW - UK Clinical Biochemistry Unit [email protected] Canterbury Health Laboratories PO Box 151, Christchurch, Standardization and Harmonization Section New Zealand [email protected] Elvar Theodorsson Department of Clinical Chemistry Immunology Section & Department of Clinical Joanna Sheldon and Experimental Medicine Protein Reference Unit, St. George’s Hospital, Linköping University Blackshaw Road, London SW17 0NH - UK SE-581 85 Linköping, Sweden [email protected] [email protected]

CONTENTS: INTRODUCTION SECTION A: Laboratory Organisation and Management Section A1. Laboratory Principles and Procedures: Learning Objectives Section A2. Senior Laboratory Management: Learning Objectives Section A3. Evidence Based Laboratory Medicine (EBLM): Learning Objectives Section A4. Conducting Research in Laboratory Medicine: Learning Objectives

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SECTION B: Analytical Section Section B1. Generic Laboratory Equipment: Learning Objectives Section B2. Basic Techniques: Learning Objectives Section B3. Laboratory Instruments – Routine: Learning Objectives Section B4. Laboratory Instruments – Spectroscopy: Learning Objectives Section B5. Laboratory Instruments – Electrophoresis: Learning Objectives Section B6. Laboratory Instruments – Chromatography: Learning Objectives Section B7. Laboratory Instruments – X-Mass Spectrometry: Learning Objectives Section B8. Laboratory Instruments – Not otherwise classified: Learning Objectives Section B9. Analytes: Learning Objectives Section B10. Laboratory Calculations: Learning Objectives Section B11. Standardization, Traceability and Harmonization Learning Objectives

SECTION C: Clinical Section Section C1. Fluid and Disorders: Learning Objectives Section C2. Acid-Base Regulation and Pulmonary Function: Learning Objectives Section C3. Disorders of Kidney and Urinary Tract: Learning Objectives Section C4. Immunology: Learning Objectives Section C5. Diabetes Mellitus: Learning Objectives Section C6. Gastrointestinal and Pancreatic Disease: Learning Objectives Section C7. Hepatobiliary Disease: Learning Objectives Section C8. Lipids and Disorders of Lipoprotein : Learning Objectives Section C9. Cardiovascular Disorders and Hypertension: Learning Objectives Section C10. , Magnesium, Parathyroid, Bone Disorders: Learning Objectives Section C11. Iron and Haemoglobin Disorders, including the Porphyria’s: Learning Objectives Section C12. Vitamins and Trace Elements: Learning Objectives Section C13. Pregnancy and Prenatal Diagnosis: Learning Objectives Section C14. General Paediatric Clinical Chemistry: Learning Objectives Section C15. Inborn Errors of Metabolism: Learning Objectives Section C16. Endocrinology: Learning Objectives Section C17. Neurological and Psychiatric Disorders: Learning Objectives Section C18. Biochemical Aspects of Monitoring Malignant Disease: Learning Objectives Section C19. Musculoskeletal Diseases: Learning Objectives Section C20. Therapeutic Drug Monitoring and Toxicology: Learning Objectives

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INTRODUCTION The IFCC curriculum is being developed as a guide for its member societies in their development of syllabuses for postgraduate trainees in laboratory medicine, appropriate for use in their own coun- tries. The curriculum should be viewed as a framework into which requirements specific to different regional or national practice can be incorporated. It is also intended to provide a resource for trainees in planning their private study in preparation for academic and professional qualifications which lead to formal recognition of expertise and status as experts and leaders in the field of laboratory medicine. The curriculum has been developed in response to a request from some National Societies, by the Committee on Distance Learning (C-DL) and will inform the development of the IFCC e-Academy. The C-DL is grateful to the following National Societies who responded to the call in 2013 and submitted their own curricula for us to consult in considering format and content: • Australia and New Zealand • Canada • Croatia • Netherlands • Romania • Slovak Republic • South Korea • Sweden • Switzerland A laboratory medicine expert is expected to have a comprehensive knowledge of the science and med- icine on which the specialty is based and to use this knowledge to develop and provide a safe, effec- tive, efficient and high quality service to its users. The curriculum is designed to provide a framework of learning both practical and theoretical components through which this expertise can be achieved. Herein, is phase 1 of the IFCC curriculum to support ongoing education in laboratory medicine. It is not intended to include references in this curriculum. Instead, the learning objectives are designed to link back to the online learning material of the IFCC eAcademy where relevant additional reading will be provided within these presentations, Figure 1.

Learning Skills IFCC recommends a stepwise approach to the acquisition and application of knowledge by trainees. Bloom’s taxonomy defines six categories and cognitive processes, refined in 20011. Each category is shown with appropriate verbs that may be used to construct learning objectives or assessment questions. • Remembering - retrieving, recognizing, and recalling relevant knowledge Define, memorise, list, name

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• Understanding - constructing meaning through interpreting, exemplifying, classifying, summarizing, inferring, comparing, and explaining Restate, discuss, describe, identify, report, explain, review, recognise • Applying - carrying out or using a procedure through executing, or implementing Translate, interpret, apply, illustrate, demonstrate, use • Analysing - breaking information into parts to explore understanding and relationships through differentiating, organizing, and attributing Distinguish, differentiate, appraise, analyse, calculate, compare, contrast • Evaluating - making judgements based on criteria and standards through checking and critiquing Appraise, evaluate, revise, score, estimate, choose, assess • Creating - putting elements together to form a coherent or functional whole; generating new ideas, products or ways of viewing things Compose, plan, propose, design, prepare, organise

Figure I In diagrammatic form, the learning process, creating and evaluating are key functions for those in the most senior professional roles.

1 Bloom B S (ed.) (1956) Taxonomy of Educational Objectives, the classification of educational goals – Handbook I: Cognitive Domain New York: McKay)

Program Learning Objectives Many components contribute to safe and effective laboratory investigation of patients and their dis- eases. These can be summarised in Figure II.

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Figure II Program Learning Objectives - Summarised

Figure II. The specialist functions of a clinical scientist are: • To advise on testing protocols and the appropriateness of testing • To provide meaningful analytical results that can be used with confidence in the diagnosis and management of patients with disease. • To provide interpretation of laboratory results in the light of clinical findings in the individual patient. • To reach this level of expertise the clinical scientist must have detailed knowledge of: ◊ Human physiology, biochemistry and organ function ◊ The causes, clinical signs and symptoms of disorders of organs, systems, metabolic disease and genetic disease ◊ Laboratory analyses and testing protocols for investigation of such disorders ◊ The options for and principles of measurement of specific analytes ◊ The pre-analytical, analytical and post analytical factors that may influence testing ◊ The limitations of analyses, including specificity, sensitivity, bias and imprecision ◊ Biological variation, reference intervals and critical test results

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Clinical Interpretation Table 1 A VITAMIN C DEF acronym Clinical interpretation of laboratory re- to use as a memory prompt sults is complex and it is important to adopt a systematic approach. There must A acquired be procedures in place in the laboratory, to ensure that specimen quality can be V vascular guaranteed and that the analytical qual- I infective/inflammatory ity of the result is fit for purpose. The re- sult can then be interpreted with respect T traumatic to reference intervals, clinically critical limits or significant changes in value and A autoimmune the causes of any abnormal or unexpected laboratory results be considered. It is very M metabolic useful to have a structured approach to help interpretation of results, particularly I iatrogenic/idiopathic those that are unexpected or unfamiliar. N neoplastic Considering the possible underlying path- ological processes is an excellent starting C congenital point and using an acronym such as the one shown below, provides structure to D degenerative/developmental the thought processes and minimises the risk of missing an important element. E endocrine/environmental A useful memory prompt is “A Vitamin C F functional Def” (Table 1).

Curriculum Structure The curriculum is designed to represent the three specialties of laboratory medicine; Blood Sciences, Microbiology and Molecular Genetics. Within each of the specialities, clinical and ana- lytical aspects are considered separately and there is further breakdown of the clinical section into sub-specialties. These are then subdivided into disease groupings, based on organ system, metabolic disease and genetic disease. Within each of these groupings, individual clinical condi- tions are specified. Analytical aspects are broken down primarily into technology groupings then further into specific techniques. The whole structure is therefore presented in a hierarchical way. Laboratory Organisation and Management, common to all specialties, is considered separately. In this version (i.e. part one) of the curriculum, concepts related to Laboratory Organisation and Management and Blood Sciences (Clinical Chemistry and Immunology) have been developed. Future additions to the curriculum will include curricula related to Haematology, Microbiology, and Molecular Genetics, Figure 3.

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Figure III Summary of Curriculum Design

Curriculum

1. 2. 4. Laboratory 3. Blood Molecular Organisation & Microbiology Management Sciences Genetics

Laboratory Clinical Senior procedures & Chemistry & Haematology Management principles Immunology

Analytical Clinical

Clinical Instrumentation TDM & Analytes Calculations Chemistry & & methodology Toxicology Immunology

Clinical TDM & Immunology Chemistry Toxicology

Figure III: • The sections covered in version 1 of the curriculum are shown in blue. • The yellow cells indicate areas of the curriculum to be developed further as part of future versions.

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An lyt s alcu ation hodologIFCC Committee for Distance Learning

The IFCC Curriculum - phase 1

SECTION A: LABORATORY ORGANISATION AND MANAGEMENT Laboratory Organisation and Management skills and concepts are considered in two categories, those which are relevant to all laboratory staff and those which are required by those in senior laboratory roles who have responsibilities for leadership in all aspects of the service. Figure A1 HierarchicalF gure A1: Hierarc structure ical of Laboratory Organisation and Management section of the curriculum

Laboratory Organisation & Management

Laboratory Senior management procedures and principles

Section A1. Laboratory Principles and • Health and safety issues Procedures: Learning Objectives • Internal quality control (IQC) Be able to discuss and demonstrate specific • Laboratory safety skills and competences for laboratory organisa- tion and management • Method evaluation • Basic information communication • Patient safety technology (ICT) skills • Pre-analytical variables • Basic instrument and equipment • Reference intervals (RI) maintenance • Basic research skills • Specimen collection • Basic statistical techniques • Specimen preparation • Biological variation • Standard curves • Document control • Standard operating procedures • External quality assessment (EQA) • Temperature monitoring

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• Waste management Section A3. Evidence Based Laboratory Medicine (EBLM): Learning Objectives • Water purity monitoring Be able to discuss the relevance of evidence Section A2. Senior Laboratory based laboratory medicine as applied to your Management: Learning Objectives organisation at an advanced level Be able to discuss and demonstrate specific Core topics skills and competences for laboratory organ- • Economic Evaluation of Diagnostic Tests isation and management at a senior or ad- vanced level • Evaluating the literature: Appraisal instruments; e.g. STEP • Accreditation and ISO15189 • Evidence Based Laboratory Medicine • Advanced communication skills (EBLM): definition, how it differs from • Advanced research skills Evidence Based Medicine (EBM) and why we need it • Budget management • The EBLM process: Ask, Acquire, Appraise; • Clinical and professional liaison Act, Audit • Evidence-based laboratory medicine • Formulation of the Question (PICO; CAPO • Facilitating training and continuing and other formats) professional development (CPD) for all • Guideline development, levels of evidence department staff and appraisal. AGREE instrument • Initiation of and collaboration in research • Laboratory Medicine and Clinical activities Outcomes; Applying the Evidence • Instrumentation and method selection • Meta-analysis • Laboratory information systems (LIS), • The Role of Clinical Audit hospital information systems (HIS) and • Searching the Evidence; PubMed; EMBASE; interfaces Cochrane Library • Medico-legal requirement and legislation • Sources of bias in studies of diagnostic • Personnel management accuracy, STARD criteria • Study design: cross-sectional, cohort and • Point of care testing policies and randomized controlled trials (RCTs) management • Systematic Reviews versus Narrative • Professional ethics Reviews • Requesting and reporting policies • Sources of Guidelines. Cochrane • System design Collaboration • Total quality management and quality EBLM: measures of diagnostic performance systems • Sensitivity, Specificity, Predictive Value, • Traceability Effect of Prevalence

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• Likelihood Ratios (and their utility), Odds • To explain research supervision and Ratios – Fagan’s nomogram mentoring • Receiver Operating Characteristic (ROC) Conduct a literature search Curve analysis • To describe literature study Evidence Based Laboratory Medicine • To explain the questions to be asked when and Point of Care Testing (POCT) reading a research publication • Outcomes of relevance for laboratory tests, • To recognise the importance of critical including POCT appraisal • Examples of evidence base for POCT includ- • To discuss how critical appraisal of research ing HbA1c, the Emergency Department, publications is undertaken self-monitoring of blood and INR testing Formulating a research plan • POCT testing and rural health; ex- • To discuss the research question amples from Australia • To explain the importance of hypothesis • POCT in the Primary Care environment based research • To describe the construction of aims and Section A4. Conducting Research in objectives Laboratory Medicine: Learning Objectives • To consider the research design Be able to discuss the key aspects related to the conduct of research in laboratory medicine Submitting a research proposal for external approval and funding Why is research in laboratory or formulating a research plan medicine important? • To recognise the importance of preparation • To describe medical research for a research proposal • To discuss the types of medical research • To discuss ten steps on the road to success that are undertaken • To describe the structure of a research • To define laboratory medicine in the context proposal of the research guide • To evaluate feedback from a submitted re- • To explain why research in laboratory medi- search proposal cine is important to stakeholder groups Conducting a research investigation Choice of suitable project and analysing findings • To describe factors that stimulate research • To explain the importance of planning for projects research implementation • To discuss how the importance of research • To describe conducting and recording- re may be assessed search investigations • To consider the practicability of a research • To discuss the analysis of results and the use project of statistics

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• To describe the drawing of conclusions from Specialist Clinical Laboratories. It is expected results that practical experience and competence in the use of generic laboratory equipment, ba- Writing research papers to publish sic techniques and laboratory equipment will • To recognise the objectives to publish be acquired in the workplace as appropriate. research results See Figure B1 for Hierarchical structure of Blood • To recognise the initial preparation in Sciences as related to Clinical Chemistry and writing research paper for publication Immunology section specifically related to the • To recognise the importance of all contents analytical component of the curriculum. in a manuscript The clinical component is shown in yellow to • To recognise ethical considerations in demonstrate the relationship between the ana- medical research lytical and clinical sections; which is presented separately in section C. Delivering research findings as oral presentations Section B1. Generic Laboratory Equipment: • To recognise the importance of presenting Learning Objectives research findings Be able to discuss the basic principle of use of • To provide guidance on preparing to generic laboratory equipment: present research findings • Balances • To describe good practice in oral • Centrifuges presentations • Microscopes • To describe good practice in poster presentations • pH meters • Quantities and Units Auditing Research and planning for the future • Waterbaths • To describe audit • To explain the process of auditing research Section B2. Basic Techniques: Learning Objectives • To describe how audit findings should be recorded and analysed Be able to discuss the basic techniques as ap- • To discuss planning for the future plied in laboratory medicine • Buffer preparation SECTION B: ANALYTICAL SECTION • Calculations The Analytical section is sub-divided into ◊ Basic statistics of central tendency ‘Instrumentation and Methodology’ and ◊ Basic statistics of dispersion ‘Analytes’ represented as follows for Clinical Chemistry and Immunology. From this sec- ◊ Addition dilution tion you should aim to be able to discuss the ◊ Serial dilution method principle and potential advantages and limitations of instruments and analyti- • Centrifugation cal techniques commonly used in Core and • Dialysis

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• Extraction techniques • ◊ Liquid-liquid • Freeze drying ◊ Solid Phase • Pipetting ◊ Supported liquid • • Extractions • Volumetric measurement

Figure B1 Hierarchical structure of Blood Sciences as related to Clinical Chemistry and Immunology (related to the analytical component) C l

Blood Sciences

Clinical Chemistry and immunology

Analytical Clinical

Instrumentation Analytes Calculations and Methodology

Figure B1: • Hierarchical structure of Blood Sciences as related to Clinical Chemistry and Immunology section specifically related to the analytical component of the curriculum. • The clinical component is shown in yellow to demonstrate the relationship between the analytical and clinical sections; which is presented separately in section C.

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• Weighing ◊ Cellulose acetate ◊ Isoelectric focusing (IEF) Section B3. Laboratory Instruments – Routine: Learning Objectives ◊ Immunofixation Be able to discuss the method principle and ◊ Isotachophoresis potential advantages and limitations of instru- ◊ Polyacrylamide ments and analytical techniques commonly used in a Core Laboratory Section B6. Laboratory Instruments – • Absorption, nephelometry and turbidimetry Chromatography: Learning Objectives • Acid-base measurement Be able to discuss the method principle and potential advantages and limitations of instru- • Immunoassay and detection systems ments and analytical techniques commonly • Ion selective electrodes used in Specialist Clinical Laboratories • Main analyser platforms and automation. • Chromatography • Osmometry ◊ Affinity ◊ Column Section B4. Laboratory Instruments – Spectroscopy: Learning Objectives ◊ Direct and reverse phase liquid chromatography Be able to discuss the method principle and potential advantages and limitations of instru- ◊ Gas chromatography ments and analytical techniques commonly ◊ Gas vs liquid chromatography used in Specialist Clinical Laboratories ◊ High-performance liquid • Luminescence and fluorescence chromatography • Spectrophotometry ◊ Ion-exchange • Spectrophotometry and ICP-MS ◊ High pressure liquid chromatography ◊ Atomic absorption (HPLC) ◊ Flame emission photometry ◊ Partition techniques ◊ Planar Section B5. Laboratory Instruments – Electrophoresis: Learning Objectives ◊ Principles of chromatography ◊ Size exclusion techniques Be able to discuss the method principle and potential advantages and limitations of instru- Section B7. Laboratory Instruments – ments and analytical techniques commonly X-Mass Spectrometry: Learning Objectives used in Specialist Clinical Laboratories MS - Basic Concepts • Electrophoresis Describe the basic principles of mass spec- ◊ 2-dimensional trometry (MS) ◊ Agarose Explain the mass to charge ratio and mass ◊ Capillary zone spectra

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Outline the components of a mass spec- • Dilute and shoot trometer, including ionisation sources (elec- • Liquid-liquid extraction (LLE) tron impact, chemical ionisation, electro- spray ionisation), mass filters (quadruple, • Protein precipitation magnetic), detectors • Supported liquid extraction (SLE) • Mass spectrometry • Solid phase extraction (SPE) ◊ Chromatographic separation (see above) Analytical – chromatography ◊ Gas Chromatography-MS (GC-MS) Discuss the processes of chromatographic sepa- ◊ Inductively Coupled Plasma MS (ICP-MS) ration including the selection of columns and ◊ Liquid Chromatography MS (LC-MS) mobile phases ◊ LC-MS-MS Define the terms isomer and epimer and explain the importance of chromatographic separation ◊ Matrix Assisted Laser Desorption/ Ionization – Time of Flight (MALDI-TOF) Analytical - quality Discuss the past, current and potential future Discuss the important considerations to sup- clinical applications of mass spectrometers, port analytical quality including full scan, selective ion monitoring, • Calibrators including traceability and multiple reaction monitoring, TOF commutability Instrumentation • External Quality Assurance (EQA) Critically discuss and compare mass spec- • Interferences trometry instruments in terms of their place • Internal quality control (IQC) in clinical testing along with advantage and limitations • Internal standard selection, including non- isotopic, deuterated and carbon 13 • GC- with single or tandem quadrupoles • Post implementation quality assessment • High- resolution MS • Qualitative scans • ICP-MS • Quantifiers and qualifier selection • LC-MS/MS with single or tandem quadrupoles • Quantitation – calibration curves • MALDI-TOF Post analytical • Orbitrap Discuss the implementation of mass spectrom- • Quadrupole – TOF (Q-TOF) etry reference intervals Outline the criteria for accepting an analyti- Principles of Analysis X-MS cal run Sample Preparation Outline the requirements of reporting a result Critically discuss the approaches to sample preparation in clinical testing along with- ad Setting up a LC-MS/MS assay vantage and limitations of each Critically discuss the pre implementation qual- • Derivatisation ity assessment i.e. method validation required.

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Critically discuss the role and selection of • Saliva mass spectrometry instruments in terms of • automation and processes. • Fully automated solutions Section B8. Laboratory Instruments – Not • Kit-user setting otherwise classified: Learning Objectives • Lab developed tests Be able to discuss the method principle and potential advantages and limitations of instru- • Near patient testing ments and analytical techniques commonly • Identification, optimisation, qualitative used in Specialist Clinical Laboratories assessment, sample preparation to full quantitation • Cell counters Applications • Emerging technologies, Discuss the clinical applications of mass ◊ Multiplex analysis spectrometry ◊ Nuclear magnetic resonance (NMR) • spectroscopy • Drug of abuse testing ◊ Sensors • Genomics • Enzymology • Glycated haemoglobin • Flow cytometry • Inborn errors of metabolism • Isotopic techniques • Metabolomics - Translation from discovery phase to targeted assays and clinical practice Section B9. Analytes: Learning Objectives • Microbiology Be able to identify the clinical relevance of each of these analytes (as applied in Section C) • Non-peptide hormones Be able to discussion the basic methods, in- • Peptide hormones cluding their advantages and limitations, that • Proteomics could be used for the analysis of common ana- • Therapeutic drug monitoring lytics measured in laboratory medicine • Toxicology including General unknowns Be able to discuss the matrix or matrices (in- screen – targeted MS/MS or high-resolu- cluding their advantages and limitations) used tions MS for measuring a particular analyte • Vitamins Lung Discuss the application of mass spectrometry • in a variety of clinical matrices • • Blood including and plasma • pCO • Dried blood spots 2 • pH • Misc e.g. dried urine, dried saliva spots, hair,

vitreous humour • pO2

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Renal Heart - muscle • Aluminium • B-type natriuretic peptide (BNP) and • Cystatin C Pro-BNP • • Creatinine • (CK) • Inulin • CK-MB • Potassium • High density lipoprotein (HDL) • Sodium • Low density lipoprotein (LDL) • Urea • pCO • Uric acid 2 • • Urine albumin • Troponin I • Urine creatinine • Troponin T • Urine protein Bone Liver • 1,25 di hydroxy vitamin D • Albumin • Calcium • Alkaine phopstase (ALP) • Magnesium • Alanine Aminotransferase (ALT) • Phosphate • Aspartate Aminotransferase (AST) • Parathyroid hormone (PTH) • Bile acids • Vitamin D (25 hydroxy vitamin D) • Endocrinology - Pituitary ◊ Total • Adrenocorticotropic hormone (ACTH) ◊ Conjugated or Direct • Growth hormone (GH) ◊ Unconjugated or Indirect • Follicle stimulating hormone (FSH) ◊ Fractions • Luteinizing hormone (LH) • Gamma-Glutamyl Transferase (GGT) • Thyroid stimulating hormone (TSH) • Insulin like growth factor (IGF)-1 Endocrinology - Peripheral • (LDH) • 17 hydroxyprogesterone • Total protein • Metabolism • Anti-mullerian hormone (AMH) • Ammonia • Cortisol • Glucose • Dehydroepiandrosterone (DHEA) • Lactate • DHEA sulfate (DHEA-S) • HbA1c • Estradiol

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• free triiodothyronine (fT3) • Phorphyrin screen • free thyroxine (fT4) • Selenium • Insulin like growth factor I (IGF-I) • Vasoactive intestinal peptide (VIP) • IGF binding protein 3 (BP3) • Vitamin A - retinol • Inhibin • Vitamin B1 • Progesterone • Vitamin B2 • Steroid hormone profiles • Vitamin B3 • Sex hormone binding globulin (SHBG) • Vitamin B6 • Testosterone • Vitamin B9 – folate Dynamic Function Tests • Vitamin B12 • Dexamethasone suppression • Vitamin C • Glucagon stimulation Test • Vitamin D • Growth hormone releasing hormone • Vitamin E (GHRH)-Arginine Test • Vitamin K • Insulin Tolerance Test • • Metyrapone Suppression Test • Zinc • Oral Glucose Tolerance Test (OGTT) Biomarkers of Cancer • OGTT for growth hormone (GH) suppression • Alpha foeto protein • Synacthen stimulation • 5-hydroxyindoleacetic acid (5HIAA) • Water deprivation Gastrointestinal - nutrition • Carbohydrate antigen (CA) 19-9 • • CA125 • Ceruloplasmin • Calcitonin • Copper • Catecholamines • Faecal calprotectin • Carcinoembryonic antigen (CEA) • Faecal elastase • Chromogranin A • • Homovanillic acid (HVA) • Insulin • Prostate specific antigen (PSA) • Intestinal permeability • Thyroglobulin • Iodine Therapeutic Drug Monitoring and Toxicology • Iron • Acetominophen (paracetamol) • Lead • Carbamazepine • • Carbon monoxide

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• Cyclosporine • IgG subclasses • Digoxin • Immunosubtraction/immunotyping • • Lymphocyte subsets • • Monoclonal protein quantification • Lithium • Oligoclonal banding (isoelectric focusing) • Mycophenolic acid • Prealbumin (transthyretin) • • Rheumatoid factor • Methotrexate • Serum and urine protein electrophoresis • Phenytoin • Serum free light chains • Salicylate • Total complement activity (CH50) • Saliva drug screen • Transthyretin (prealbumin) • Sirolimus • Tryptase • Tacrolimus Autoantibodies • Theophylline • Acetyl choline receptor • Urine drugs of abuse screening • Adrenal Immunology • Antibodies associated with neurological • Albumin dis­eases (paraneoplastic antibodies) • Alpha-1-antitrypsin quantification, • Centromere phenotyping and genotyping • Cyclic citrullinated peptide • Beta -2 microglobulin • Double stranded DNA • C1 esterase inhibitor • Endomysium • Total complement activity (CH50) • Extractable nuclear antigens • Complement C3 and C4 ◊ SSA (Ro) • C-reactive protein (CRP) ◊ SSB (La) • Cryoglobulins ◊ Ribo nuclear protein (RNP) • Full blood count ◊ Sm • Haptoglobin ◊ Jo1 • Hepatitis A, B and C ◊ SCL70 • HIV serology ◊ Scl Sm • IgE and specific IgE • Gliadin • Immunofixation electrophoresis (IFE) • Glomerular basement membrane • Immunoglobulins (IgA, IgG, IgM) • Intrinsic factor • IgD • Liver

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◊ Liver kidney microsomal • Estimated glomerular filtration rate (eGFR) ◊ Mitochondrial • Globulins ◊ Smooth muscle • INR • Neutrophil cytoplasm (ANCA) • LDL ◊ Myeloperoxidase • (including calculated osmolarity) ◊ Proteinase 3 Be able to perform basic statical calculations • Nuclear components (ANA) used in the laboratory. • Ovary Be able to distinguish the appropriate statisti- • cal tests to employ based on the distribution of the data. ◊ Glutamic acid decarboxylase • Bias ◊ Insulin • Biological variation ◊ Insulinoma antigen 2 (IA-2) • Evaluation of differences between ◊ Zinc Transporter 8 (ZnT8) populations • Skin • Measures of central tendency ◊ Basement membrane • Measures of dispersion ◊ Intercellular cement • Multiple of Median (MOM) • Thyroid • Positive and negative predictive value ◊ Microsomal • Reference interval ◊ Peroxidase/microsomal • Recovery ◊ Thyroglobulin • Sigma ◊ TSH receptor • Uncertainty of measurement • Tissue transglutaminase Section B11. Standardization, Traceability Section B10. Laboratory Calculations: and Harmonization Learning Objectives Learning Objectives Core topics Be able to discuss the process for calculating common equations relevant to laboratory Understand why different methods for the medicine same analyte give different results • Addition dilution Explain why reducing between-method vari- • ability is important • Bicarbonate Describe traceability in laboratory medicine • Converting between mass and molar units List the stakeholders involved in achieving • Corrected calcium traceability in laboratory medicine together • Corrected sodium with their respective roles

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Advanced • Clinical assessment of ECF volume Standardization in general vs standardization • Extracellular and intracellular fluid volumes in the metrology of chemistry • Hormonal control of fluid and electrolyte Understanding the concept of “amount of sub- balance (, angiotensin, aldosterone, stance” and its unit the mole ADH) Understand the concept “measurand” • Principles of correcting fluid and electrolyte The meaning of comparisons in measurement losses Traceability as a property of the measurement Disorders and disease states result To understand the causes, clinical signs and Standardisation in the analytical phase and in symptoms of the following features of disorders the pre-and post-analytical phases of the total relating to fluid and electrolyte metabolism. testing chain To describe which laboratory investigations Harmonisation and the importance of are important in their detection, diagnosis and commutability management Standardisation as a top-down regulatory pro- • Dehydration cess which is stable in time and space • Diabetes insipidus Harmonisation as a bottom up consensus pro- • (ECF) volume loss cess based on commutable patient samples • Hypernatremia and with less stability than standardisation in time and space • Hyperkalemia and pseudohyperkalemia Examples of harmonisation projects • Hypokalemia • Hyponatremia and pseudohyponatraemia SECTION C: CLINICAL SECTION • Shock In laboratory medicine it is essential for pro- • Syndrome of inappropriate antidiuretic hor- fessionals to have a sound understanding of mone (SIADH) both analytical tools to achieve the best clini- cal outcomes. It is therefore essential that Specific Laboratory Investigations laboratory professionals have a sound working To gain an in depth knowledge of the following knowledge of physiology and specific laboratory investigations important to related to their testing area. This section of the study of fluid and electrolyte disorders. the curriculum details the clinical areas related to clinical chemistry and immunology as de- To be familiar with analytical methods avail- tailed in Figure C1. able for their measurement To be able to select laboratory investigations Section C1. Fluid and Electrolyte Disorders: and interpret the analytical results in the light Learning Objectives of the clinical signs and symptoms in the indi- Basic Concepts vidual patient To understand the principles and control of • Aldosterone fluid and electrolyte balance: • (sodium, potassium, chloride)

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Figure C1 Hierarchical structure of Blood Sciences as related Fi C1: Hie chic l to Clinical Chemistry and Immunology (Clinical component)

Blood Sciences

Clinical Chemistry and immunology

Analytical Clinical

Clinical Chemistry and Therapeutic Drug Immunology Monitoring and Toxicology

Figure C1: • Hierarchical structure of Blood Sciences as related to Clinical Chemistry and Immunology section specifically related to the clinical component of the curriculum. • The analytical component is shown in yellow to demonstrate the relationship between the ana- lytical and clinical sections; which was presented separately in section B.

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• Serum and • Respiratory alkalosis • Renin-angiotensin axis (RTA) assessment Specific Laboratory Investigations • Urine and faecal electrolytes To gain an in depth knowledge of the following specific laboratory investigations important to Section C2. Acid-Base Regulation and the study of acid-base balance and pulmonary Pulmonary Function: Learning Objectives function. Basic Concepts To be familiar with analytical methods avail- To understand the principles and control of able for their measurement acid – base balance and pulmonary function To be able to select laboratory investigations • Anion gap and interpret the analytical results in the light of the clinical signs and symptoms in the indi- • Compensation for acidosis and alkalosis vidual patient • Control of respiration • Alcohols (ethanol, methanol, ethylene • Henderson-Hasselbach equation glycol, isopropanol) • Haemoglobin dissociation curves and limi- • Anion gap tations of calculated oxygen saturation • Blood gas and hydrogen ion measurements • Osmol gap • Co-oximetry (carboxyhaemoglobin and • Systematic approach to investigating acid- methaemoglobin) base disturbances • Calculated blood gas parameters and their Disorders and disease states limitations To understand the causes, clinical signs and • Ketones (urine and serum) symptoms of the following features of disor- • Lactate ders relating to acid-base balance and pulmo- • Osmolality nary function. • Osmol gap To describe which laboratory investigations are important in their detection, diagnosis and • Salicylate management Section C3. Disorders of Kidney and • Alpha 1 antitrypsin (A1AT) deficiency (see Urinary Tract: Learning Objectives also Section C7, Hepatobiliary disease) Basic concepts • Carbon monoxide poisoning To understand the principles and control of • renal function and the urinary tract, -includ • Metabolic alkalosis ing renal stones and purine and pyrimidine • Pyloric stenosis metabolism • Renal tubular acidosis (see also Section 3, • (creatinine, cystatin C, inulin) Disorders of kidney and urinary tract) • Creatinine standardisation • Respiratory acidosis • Disorders and disease states

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• Estimated glomerular filtration rate (eGFR) • Systemic lupus erythematosus (SLE) calculations • Urinary tract infection (UTI) • Endocrine functions of the kidney • Types of renal stone • Formation of renal calculi • Uraemia • Haemodialysis • Vasculitis (ANCA associated) • Peritoneal dialysis Specific Laboratory Investigations • Proteinuria; glomerular permeability, tubu- To gain an in depth knowledge of the following lar proteinuria specific laboratory investigations important to • Renal stone formation the study of renal function, the urinary tract • Steady state renal function and uric acid metabolism • Transplant biochemistry To be familiar with analytical methods avail- able for their measurement To understand the causes, clinical signs and symptoms of the following features of disor- To be able to select laboratory investigations ders relating to renal function, the urinary and interpret the analytical results in the light tract and uric acid metabolism of the clinical signs and symptoms in the indi- vidual patient To describe which laboratory investigations are important in their detection, diagnosis and • Antinulear antibodies (ANA) management • ANCA • Acute kidney injury • Beta 2 microglobulin • Amyloid • Complement C3 and C4 • Antineutrophil cytoplasmic antibodies • Creatinine (serum and urine) (ANCA) associated vasculitis • Cryoglobulins • Chronic kidney disease • Cystatin C • Cryoglobulin associated renal damage • • Drug-induced renal damage • Examination and identification of renal • Glomerulonephritis calculi • Goodpasture’s syndrome • Measurement of immunosuppressant drugs • Gout (cyclosporine, tacrolimus, sirolimus) • Hyperuricaemia • Phosphate, calcium and magnesium • Myeloma associated renal damage • Renal calculi analysis • Nephritic syndrome • Serum and urine electrophoresis and immunoglobulins • Nephrotic syndrome • Urea and urea kinetics • Renal tubular acidosis (see also Section 2: Acid-base regulation and pulmonary • Uric acid function) • Urine albumin

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• Urine dip stick analysis Disorders and disease states • Urine microscopic analysis To understand the causes, clinical signs and • Urine oxalate symptoms of the following features of disor- ders relating to the immune system Section C4. Immunology: To describe which laboratory investigations Learning Objectives are important in their detection, diagnosis and Basic concepts management To understand the principles, components and • Allergy and anaphylaxis control of the immune system • Autoimmune diseases Components of the immune system (Cells, ◊ Endocrine Lymphoid tissue, Soluble components and mediators) ◊ Gastro intestinal (GI) tract • Acute phase response ◊ Liver • Adaptive Immune system ◊ Renal • Complement ◊ Rheumatic and articular ◊ Alternative pathway ◊ Skin ◊ Classical pathway • Lymphoid malignancy ◊ Mannose-binding lectin (MBL) pathway ◊ B cell • Cytokines ◊ T cell ◊ Colony stimulating factors and • Primary immune deficiency haematopoietic • Secondary immune deficiency ◊ Interferons • Transplantation ◊ Interleukins Specific Laboratory Investigations ◊ Tumour necrosis factors To gain an in depth knowledge of the following • Hypersensitivity reactions specific laboratory investigations important to ◊ Types I – IV (or V) the study of disorders of the immune system • Immunoglobulins To be familiar with analytical methods avail- ◊ Function able for their measurement ◊ Gene rearrangement To be able to select laboratory investigations and interpret the analytical results in the light ◊ Structure of the clinical signs and symptoms in the indi- • Innate Immune system vidual patient • Lymphocytes • Autoantibodies to ◊ B lymphocytes ◊ Skin basement membrane, intercellular ◊ T lymphocytes cement

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◊ Nuclear (ANA), smooth muscle, • Self-monitoring of blood glucose mitochondrial Disorders and disease states ◊ Neutrophil cytoplasmic (ANCA), To understand the causes, clinical signs and glomerular basement membrane, ANA symptoms of the following aspects of diabe- ◊ Rheumatoid factor, cyclic citrullinated tes mellitus peptides, nuclear, double stranded To describe which laboratory investigations DNA, extractable nuclear antigens are important in their detection, diagnosis ◊ Thyroid, pancreas, adrenal, ovary, and management (testis) • Diabetic ketoacidosis ◊ Tissue transglutaminase, endomysial, • Gestational diabetes intrinsic factor • Hypoglycaemia • Full blood count • Metabolic syndrome • HLA typing • Non-ketotic hyperosmolar coma • Immunoglobulin quantification and IgG • Type I diabetes subclasses • Type 2 diabetes • Lymphocyte subsets (CD3, 4, 8, 16/56, 19) • Monoclonal protein identification and quan- Specific Laboratory Investigations tification in serum and urine To gain an in depth knowledge of the following • Total and specific IgE specific laboratory investigations important to the study of diabetes mellitus • Tryptase To be familiar with analytical methods avail- Section C5. Diabetes Mellitus: able for their measurement Learning Objectives To be able to select laboratory investigations Basic concepts and interpret the analytical results in the light of the clinical signs and symptoms in the indi- To understand the pathogenesis of diabetic vidual patient states and the following aspects of the study • Anti-glutamic acid decarboxylase (GAD) of diabetes mellitus antibodies • Aetiology of Type I, Type 2 and gestational • Anti insulin antibodies diabetes • Blood gas and hydrogen ion measurements • Complications of diabetes (microvascular, macrovascular) • C-peptide • Diabetic ketoacidosis • and other glycated proteins • HbA1c standardisation • Glucagon • Guidelines for the screening, diagnosis and • Glucose monitoring of diabetes • Glucose tolerance tests • Non-ketotic hyperosmolar coma • HbA1c

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• Insulin • H. pylori infection • Insulinoma antigen 2 (IA-2) • Intestinal malabsorption, including vita- • Ketones, (β-hydroxy butyrate) mins, (see also Section 5 : trace elements and vitamins) • Microalbumin • Neuroendocrine tumours • Zinc Transporter 8 (ZnT8) • Pyloric stenosis (see also Section 2, Acid Section C6. Gastrointestinal and Pancreatic base regulation and pulmonary function) Disease: Learning Objectives • Pernicious anaemia Basic concepts • Zollinger-Ellison syndrome To understand the principles and control of Specific Laboratory Investigations gastrointestinal and pancreatic function To gain an in depth knowledge of the follow- • Acute and chronic pancreatitis ing specific laboratory investigations -impor tant to the study of disorders of gastrointesti- • Autoimmune bowel disease nal and pancreatic function • Bowel cancer screening To be familiar with analytical methods avail- • Causes of gastric ulceration able for their measurement • Endocrine and exocrine functions of the To be able to select laboratory investigations pancreas and interpret the analytical results in the light • Inflammatory bowel disease of the clinical signs and symptoms in the indi- vidual patient • Intestinal absorption of proteins, fats and 14 carbohydrates • CO2 urea breath test for H. pylori • Neuroendocrine Tumours • Amylase and macroamylase • Vitamin B12 absorption • CA 19-9 Disorders and disease states • Carcinoembryonic antigen (CEA) To understand the causes, clinical signs and • Chromogranin A symptoms of the following features of disor- • Elastase ders relating to gastrointestinal and pancre- • Endomysial autoantibodies atic function • Faecal calprotectin To describe which laboratory investigations are important in their detection, diagnosis • Faecal occult blood and management • Hydrogen breath test for lactose intolerance • Acute and chronic pancreatitis • IgE and specific IgE • Carcinoid syndrome • Intrinsic factor antibodies • Coeliac Disease • Lipase • Crohn’s Disease • Serotonin and 5 HIAA • Food allergy • Transglutaminase autoantibodies

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• Vitamin B12 and folate • Chronic hepatitis • Xylose absorption test • Cirrhosis ( Including primary biliary cirrhosis) • Elevated bilirubin levels: conjugated, Section C7. Hepatobiliary Disease: unconjugated and total Learning Objectives • Elevated neonatal bilirubin levels Basic concepts • Infectious hepatitis To understand the metabolic functions of the • Paracetamol (Acetominophen) overdose liver and the following aspects of hepatobili- ary disease Specific Laboratory Investigations • Autoimmune disease To gain an in depth knowledge of the following • Cholestasis specific laboratory investigations important to the study of disorders of hepatobiliary function • Drugs – acute and chronic To be familiar with analytical methods avail- • Genetic – e.g. A1AT deficiency (see also able for their measurement Section 2, Acid-base regulation and pulmo- To be able to select laboratory investigations nary function) and interpret the analytical results in the light • Inflammatory and infective liver disease of the clinical signs and symptoms in the indi- (hepatitis) vidual patient • Liver autoantibodies • Albumin (blood and ascites) • Liver cirrhosis • Alpha-1 antitrypsin concentration and • Liver function – synthesis, conjugation, phenotype/genotype detoxification • Alphafoetoprotein (AFP) • Liver transplantation • Ammonia • Liver tumours – primary or secondary • Bile acids • Origin, metabolism and transport of bilirubin • Bilirubin – conjugated, unconjugated, total, transcutaneous Disorders and disease states • Caeruloplasmin To understand the causes, clinical signs and • Ethanol symptoms of the following features of disor- ders relating to hepatobiliary function • Ferritin To describe which laboratory investigations • Hepatitis serology are important in their detection, diagnosis and • Iron management • Liver enzymes: ALT, AST, ALP, GGT • Acute hepatitis • Measurement of immunosuppressant drugs • Alcoholic liver disease (cyclosporine, tacrolimus, sirolimus) • Allograft rejection • Paracetamol (Acetominophen) • Biliary damage and dysfunction • PT-INR

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Section C8. Lipids and Disorders of Lipoprotein To be able to select laboratory investigations Metabolism: Learning Objectives and interpret the analytical results in the light of the clinical signs and symptoms in the indi- Basic concepts vidual patient To understand the principles and control of lip- • Apolipoprotein A and B id metabolism and the following aspects of the study of lipid and lipoprotein disorders • Genotyping of ApoE, LDL receptor and LPL • Apolipoproteins: functions, receptors (e.g. • HDL cholesterol LDL-R) • High sensitive CRP • Cardiovascular disease risk calculation and • LDL cholesterol – direct and calculated evaluation, and cost-effectiveness of lipid methods screening strategies. • Lipoprotein electrophoresis • Fatty acid transport and oxidation • Lipoprotein ultracentrifugation • Lipid absorption, transport and metabolism • Lp(a) • Lipoprotein metabolism: endogenous and exogenous pathways • Non-HDL cholesterol (calculated) Disorders and disease states • Total cholesterol To understand the causes, clinical signs and • Triglycerides symptoms of the following features of disor- Section C9. Cardiovascular Disorders and ders relating to lipid and lipoprotein disorders Hypertension: Learning Objectives To describe which laboratory investigations are important in their detection, diagnosis and Basic concepts management To understand the causes and manifestations • Atherosclerosis of the cardiovascular disease the assessment • Hypercholesterolaemia of individual risk • Hyperlipidemia • Acute coronary syndrome ◊ Inherited disorders • Cardiac risk assessment ◊ Non-inherited disorders • Myocardial infarction • Hypolipidemia Disorders and disease states • Metabolic syndrome To understand the causes, clinical signs and symptoms of the following features of car- Specific Laboratory Investigations diovascular disorders To gain an in depth knowledge of the following To describe which laboratory investigations specific laboratory investigations important to are important in their detection, diagnosis the study of disorders of lipid and lipoprotein and management metabolism To be familiar with analytical methods avail- • Atherosclerosis able for their measurement • Cardiac amyloid

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• Congestive heart failure • Regulation of calcium and phosphate levels • Hypertension Disorders and disease states • Myocardial infarction To understand the causes, clinical signs and • Stable angina symptoms of the following disorders and manifestations of calcium and phosphate me- • Unstable angina tabolism and bone disease Specific Laboratory Investigations To describe which laboratory investigations To gain an in depth knowledge of the follow- are important in their detection, diagnosis ing specific laboratory investigations -impor and management tant to the study of cardiovascular disease • Hypercalcaemia and hypertension • Hypermagnesaemia To be familiar with analytical methods avail- • Hyperparathyroidism able for their measurement • Hyperphosphataemia To be able to select laboratory investigations and interpret the analytical results in the light • Hypocalcaemia of the clinical signs and symptoms in the indi- • Hypomagnesaemia vidual patient • Hypoparathyroidism • Anti-heart muscle antibodies (Dresslers) • Hypophosphataemia • High-sensitivity CRP • Hypophosphatasia • Natriuretic peptides • Pseudohypoparathyroidism • Serum and urine electrophoresis and • Osteogenesis imperfecta immunoglobulins • Osteoporosis • Troponin and high-sensitivity troponin • Paget’s disease Section C10. Calcium, Magnesium, Parathyroid, Bone Disorders: Specific Laboratory Investigations Learning Objectives To gain an in depth knowledge of the follow- ing specific laboratory investigations impor- Basic concepts tant to the study of calcium and phosphate To understand the control of calcium and metabolism asn bone disease phosphate homeostasis including the follow- To be familiar with analytical methods avail- ing specific aspects of the process. able for their measurement • Circulating forms of calcium To be able to select laboratory investigations • Metabolism of vitamin D and interpret the analytical results in the • Markers of bone resorption and bone light of the clinical signs and symptoms in formation the individual patient • Primary versus secondary hyper/hypo • 1,25 di-hydroxy vitamin D calcaemia • 25 hydroxy vitamin D

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• C- and N-telopeptides • Glucose-6-phosphate dehydrogenase • Calcium – total and ionized (G6PD) deficiency • Magnesium • Haemochromatosis • Osteocalcin • Haemoglobinopathies • Phosphate • Intravascular haemolysis • PTH • Iron deficient anaemia • PTHrp • Thalassaemia • Pyridinolines Specific Laboratory Investigations • Total and bone-specific ALP To gain an in depth knowledge of the follow- Section C11. Iron and Haemoglobin ing specific laboratory investigations -impor Disorders, including the Porphyria’s: tant to the study of iron and haem metabo- Learning Objectives lism and the porphyrias Basic Concepts To be familiar with analytical methods avail- To understand the control and metabolism of able for their measurement iron and haem, the mechanisms which lead to To be able to select laboratory investigations iron overload and deficiency, and the implica- and interpret the analytical results in the light tions of these states. of the clinical signs and symptoms in the indi- To understand the enzymatic defects of haem vidual patient synthesis which lead to the porphyrias • Delta-aminolaevulinic acid (ALA) • Haem biosynthesis • Ferritin • Haem metabolism • Iron absorption, transport and storage • Full blood count • Iron deficiency • G6PD • Iron overload • Haptoglobin Disorders and disease states • Haemoglobin and haemoglobin variants To understand the causes, clinical signs and • Haemopexin symptoms of the following aspects and man- • Iron ifestations of disorders of iron and haem metabolism • Porphobilinogen (PBG) To describe which laboratory investigations • Porphyrins are important in their detection, diagnosis • Soluble and management • Total iron binding capacity • Acute and chronic porphyrias and their dif- ferential diagnosis • Transferrin • Anaemia secondary to malignancy •

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Section C12. Vitamins and Trace Elements: Specific Laboratory Investigations Learning Objectives To gain an in depth knowledge of the following Basic Concepts specific laboratory investigations important to the study of trace elements and vitamins To understand the importance of trace ele- ments and vitamins to metabolic processes To be familiar with analytical methods avail- and wellbeing, the mechanisms of their ac- able for their measurement tions and the consequences of deficiency and To be able to select laboratory investigations overload states. and interpret the analytical results in the light • Essential and non-essential metals of the clinical signs and symptoms in the indi- vidual patient • Fat soluble vitamins; A and carotene, D, E and K • Cadmium in blood and urine • Caeruloplasmin • Folate metabolism and function • Delta amino laevulinic acid (ALA) • Genetic disorders of copper metabolism • Ferritin • Genetic disorders of iron metabolism • Folate • Potential vitamin toxicity • Homocysteine • Toxic and non-toxic metals • Intrinsic factor antibody • Vitamin B12 absorption, metabolism and function • Laboratory assessment of specific B vitamin status • Water soluble vitamins; B group vitamins and C • Lead in blood and urine • Mercury in blood and urine Disorders and disease states • Methylmalonic Acid (MMA) To understand the causes, clinical signs and symptoms of the following aspects of disor- • Serum and urinary iron ders of trace element and vitamin metabolism • Serum and urinary copper To describe which laboratory investigations • Transferrin are important in their detection, diagnosis and • Vitamin B12 management • Vitamin D • Cadmium poisoning • Copper deficiency/excess Section C13. Pregnancy and Prenatal Diagnosis: Learning Objectives • Folate deficiency • Iron overload Basic Concepts • Lead poisoning To understand the following concepts in rela- tion to the provision of a clinical laboratory • Mercury poisoning service to support pregnancy and the health • Vitamin B12 deficiency of the mother and foetus.

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• Biochemical, haematological and endocrine Specific Laboratory Investigations changes during pregnancy To gain an in depth knowledge of the following • Changes in analyte levels throughout specific laboratory investigations important to pregnancy the study of pregnancy and foetal development ◊ Multiples of the median To be familiar with analytical methods avail- • Foetal lung maturity able for their measurement • hCG doubling time To be able to select laboratory investigations and interpret the analytical results in the • hCG forms light of the clinical signs and symptoms in • Maternal serum screening – purpose, limi- the individual patient tations, screen vs. definitive testing • AFP ◊ First trimester screening • hCG ◊ Integrated screening • Inhibin A ◊ Second trimester screening • PAPP-A • Premature rupture of membranes and • Plasme nucleic acids pre-term labour • Serum bile acids • Rh isoimmunisation • Unconjugated estriol Disorders and disease states To be able to discuss the clinical rational for To understand the causes, clinical signs and tests using amniotic fluid symptoms of the following, complications of • Acetylcholinesterase pregnancy and foetal development. • AFP To describe which laboratory investigations • Bilirubin – absorbance at 450 nm are important in their detection, diagnosis and management • Karyotype • Choriocarcinoma Section C14. General Paediatric Clinical • Ectopic pregnancy Chemistry: Learning Objectives • Gestational diabetes Basic Concepts • Molar pregnancy To understand the following special consider- • Obstetric cholestasis ations in relation to the provision of a general paediatric clinical laboratory service. • Open neural tube defects • How to collect heel prick samples • Pre-eclampsia, HELLP syndrome • Issues with capillary specimens • Rh isoimmunisation • Paediatric reference intervals – dynamic • Trisomy 21, 18 and 13 changes with growth, development and • Trophoblastic disease puberty

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• Sample volume and collection issues, in- For all analyses, sample size is of key impor- cluding sweat collection tance in method selection Disorders and disease states • Acid base / blood gases To understand the causes, clinical signs and • Calcium symptoms of the conditions which may pres- ent to a general paediatric laboratory. • Glucose To describe which laboratory investigations • Hormone measurement (see Section 16, are important in their detection, diagnosis Endocrinology) and management • Congenital thyroid disease ◊ Anterior hypothalamic hormones • Cystic fibrosis ◊ Cortisol • Delayed puberty ◊ Neuropeptides • Diabetes mellitus type 1 ◊ Ovarian hormones • Disorders of sex development, including ◊ Testicular Hormones congenital adrenal hyperplasia • Growth retardation and growth hormone ◊ Thyroid function deficiency ◊ Other adrenal hormones • Hypocalcaemia • HVA, dopamine • Inborn errors of metabolism • Performance of the sweat test • Neonatal hypoglycaemia • Neonatal jaundice • Plasma catecholamines • Neuroblastoma • Total and differential bilirubin

• Precocious puberty Result interpretation • Respiratory distress To recognise that the population-based refer- Specific Laboratory Investigations ence intervals for many of children’s chemis- To gain an in depth knowledge of the follow- tries change throughout childhood. ing specific laboratory investigations -impor tant to the study of disorders presenting in To recognise that these reference intervals the neonate and in childhood change differently for different analytes. To be familiar with analytical methods avail- To recognise some of the problems associated able for their measurement with reporting children’s chemistries. To be able to select laboratory investigations To be aware of some of the problems that and interpret the analytical results in the light of the clinical signs and symptoms in the indi- arise from failing to report correct children’s vidual patient chemistry reference intervals

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Section C15. Inborn Errors of Metabolism: To be familiar with analytical methods avail- Learning Objectives able for their measurement

Basic Concepts To be able to select laboratory investigations and interpret the analytical results in the light To understand all aspects of screening for dis- of the clinical signs and symptoms in the indi- ease including the rationale for screening and vidual patient the process. • Acylcarnitines • Challenges with newborn screening • Alpha-1-antitrypsin genotyping • Diseases appropriate for newborn screening • Amino acids – characteristics • Haemoglobin electrophoresis • Newborn screening process • Immunoreactive trypsinogen Disorders and disease states • Organic acids To understand the causes, clinical signs and • Specific enzyme testing (e.g., biotinidase, symptoms of the following inherited conditions galactokinase) To describe which laboratory investigations • Sweat chloride and conductivity are important in their detection, diagnosis and management Section C16. Endocrinology: Learning Objectives • Congenital hypothyroidism Basic Concepts • Cystic fibrosis To understand all aspects of hormone action, • Enzyme deficiencies: biotinidase, including feedback inhibition and other - con galactokinase trolling mechanisms for hormone release and • Fatty acid oxidation disorders: short, -me to acquire a detailed knowledge of the major dium, long and very long chain endocrine organs and systems. • Haemoglobinopathies Hypothalamic-pituitary axis • Homocystinuria • Anterior pituitary hormones • Lysosomal disease, glycogen storage dis- • Communication between pituitary and- hy eases: lipidoses, hexosaminidases, Fabry’s pothalamus – anterior vs. posterior disease • Hirsutism and virilisation • Maple syrup urine disease • Hypothalamic hormones • Phenylketonuria • Inhibitory hormones • Tyrosinaemia • Posterior pituitary hormones • Primary vs. secondary causes Specific Laboratory Investigations • Renin-angiotensinogen-aldosterone pathway To gain an in depth knowledge of the following specific laboratory investigations important to • Steroid biosynthesis pathway the study of inherited metabolic diseases • Stimulation tests

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• Suppression tests • 17 hydroxyprogesterone Disorders and disease states • ACTH To understand the causes, clinical signs and • ADH symptoms of the following endocrine disorders • Aldosterone, renin and ratio To describe which laboratory investigations • Androstenedione are important in their detection, diagnosis • Angiotensin converting enzyme (ACE) and management • Autoantibodies to the relevant endocrine • Acromegaly/gigantism organ • Addison’s syndrome • Catecholamines (plasma and urine) • Adrenal insufficiency • Cortisol – serum, urine, salivary • Congenital adrenal hyperplasia • Dexamethasone suppression test • Cushing’s syndrome and Cushing’s disease • DHEAS • Female infertility • Estradiol • Growth hormone deficiency • FSH • Hyperaldosteronism • Growth hormone • Hyperprolactinemia • Growth hormone suppression test (OGTT) • Hyperthyroidism • Insulin-like growth factor 1 (IGF-1) • Hypothyroidism • LH • Male infertility • Metanephrines (plasma and urine) • Phaeochromocytoma • Progesterone • Polycystic ovarian syndrome • Prolactin and macroprolactin • Premature ovarian failure • SHBG • Sheehan’s syndrome • Testosterone – total, free, bioavailable • Thyroid cancer • Thyroglobulin, anti-thyroglobulin antibodies Specific Laboratory Investigations • : TSH, Free T3, free T4 To gain an in depth knowledge of the following Total T3, Total T4 specific laboratory investigations important to • TSH receptor antibodies the study of endocrine disorders Section C17. Neurological and Psychiatric To be familiar with analytical methods avail- Disorders: Learning Objectives able for their measurement To be able to select laboratory investigations Basic Concepts and interpret the analytical results in the light To understand the following key concepts re- of the clinical signs and symptoms in the indi- lating to neurological processes and disrup- vidual patient tion of these

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• Blood brain barrier • Oligoclonal banding (isoelectric focusing) • Paraneoplastic syndromes • Paraneoplastic antibodies Disorders and disease states • Porphobilinogen (PBG) To understand the causes, clinical signs and • Porphyrins (urine, feces, serum) symptoms of the following disorders, some Section C18. of which are primary neurological disor- Biochemical Aspects of Monitoring ders and some of which have neurological Malignant Disease: Learning Objectives manifestations To describe which laboratory investigations Basic Concepts are important in their detection, diagnosis To understand the following key concepts re- and management lating to the choice, use and measurement • Acute porphyria’s of biomarkers of cancer • Alzheimer’s disease • Characteristics of an ideal biomarkers of cancer • Meningitis • Uses and limitations of current biomarkers • Multiple sclerosis of cancer • Myasthenia gravis • Uses of biomarkers of cancer: prognosis, • Paraneoplastic syndrome monitoring, recurrence Specific Laboratory Investigations Specific Laboratory Investigations To gain an in depth knowledge of the follow- To gain an in depth knowledge of the follow- ing specific laboratory investigations -impor ing specific laboratory investigations -impor tant to the study of neurological disorders tant in the management of malignant diseases To be familiar with analytical methods avail- To be familiar with analytical methods avail- able for their measurement able for their measurement To be able to select laboratory investigations To be able to select laboratory investigations and interpret the analytical results in the light and interpret the analytical results in the light of the clinical signs and symptoms in the indi- of the clinical signs and symptoms in the indi- vidual patient vidual patient • Aminolaevulinic acid (ALA) • AFP • Anti-acetylcholine receptor antibodies • ALP isoenzymes • Anti-Hu, Anti-Yo antibodies • CA 15-3 • CSF beta-2-transferrin in rhinorrhoea and • CA 19-9 otorrhoea (fistula) • CA 125 • CSF glucose • Calcitonin • CSF protein • CEA • Examination of synovial fluid • HE4

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• hCG To be familiar with analytical methods avail- • HER2/Neu able for their measurement • LDH isoenzymes To be able to select laboratory investigations and interpret the analytical results in the light • Mammary specific antigen of the clinical signs and symptoms in the indi- • PSA (total and free) vidual patient • PTHrp • Anti-CCP antibodies • Protein electrophoresis • Anti-ds DNA • Thyroglobulin, anti-thyroglobulin antibodies • Anti-neutrophilic cytoplasmic antibodies (ANCA) • Other emerging biomarks as deemed relevant • Anti-nuclear antibodies (ANA and specific antibodies SSA, SSB, Sm, RNP) Section C19. Musculoskeletal Diseases: • Rheumatoid factor Learning Objectives • Serum creatine kinase Basic concepts To understand muscle function and the use and Section C20. Therapeutic Drug Monitoring limitations of autoimmune testing in diagnosis and Toxicology: Learning Objectives • Autoimmune testing Basic Concepts • Muscle function To understand the following key concepts of pharmacology and the key factors relevant to Disorders and disease states drug action and measurement. To understand the causes, clinical signs and To understand the mode of action and clinical symptoms of the following musculoskeletal uses of drugs in the categories listed. disorders (PK) To describe which laboratory investigations • Absorption are important in their detection, diagnosis and management • Bioavailability • Duchenne / Becker dystrophy • Compliance • Osteoarthritis • Distribution • Rhabdomyolisis • Excretion • Rheumatoid arthritis • Metabolism • Systemic lupus erythematosus • Peak vs. trough drug levels • Vasculitis • Steady state Specific Laboratory Investigations Pharmacodynamics (PD) and Pharmacogenetics (PG) To gain an in depth knowledge of the following specific laboratory investigations important in • Antibiotics the management of musculoskeletal diseases • Antidepressants

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• Anti-epileptic drugs To be familiar with analytical methods avail- • Anti-psychotic drugs able for their measurement • Carbon monoxide poisoning To be able to select laboratory investigations and interpret the analytical results in the • Cardioactive drugs light of the clinical signs and symptoms in • Common drugs of abuse the individual patient • Drugs appropriate for TDM • Acetaminophen • Drug screens vs. confirmatory tests for • Carbon monoxide – carboxyhaemoglobin drugs of abuse • Cholinesterase and pseudocholinesterase • Free drugs • Cyclosporine • Immunosuppressants • Ethanol • Lithium • Ethylene glycol • Methotrexate and rescue • Isopropanol • Thiopurines • Methanol • Warfarin • Mycophenolic acid (MPA) Disorders and disease states • Osmolality To understand the causes, clinical signs and • Point-of-care drug screens symptoms of the following toxic conditions • Sirolimus and the treatment regimes which may be used, • Salicylates To describe which laboratory investigations are • Tacrolimus important in their diagnosis and management • Acetaminophen toxicity  • Carbon monoxide poisoning Acknowledgements • Ethanol, alcohol toxicity In addition to the curriculums generously sub- mitted by IFCC member societies for review, we • Organophosphate poisoning wish to acknowledge The European Federation • Salicylate toxicity of Clinical Chemistry and Laboratory Medicine’s (EFLM) comprehensive syllabus, which has been Specific Laboratory Investigations designed for use in Europe. Wieringa G et al. To gain an in depth knowledge of the follow- The EC4 European Syllabus for Post-Graduate ing specific laboratory investigations -impor Training in Clinical Chemistry and Laboratory tant in for drug monitoring and detection of Medicine: version 4-2012. Clin Chem Lab Med toxic concentrations of drugs 2012;50(8):1317-1328

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