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This document provides a table of contents for the book "Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics". The table of contents lists 50 chapters organized into 6 parts that cover topics such as principles of laboratory medicine, analytical techniques and instrumentation, analytes, pathophysiology, molecular diagnostics, and reference information.

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PART I PRINCIPLES OF LABORATORY MEDICINE, 1 1 . Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine, 1 2 . Selection and Analytical Evaluation of Methods—With Statistical Techniques, 6 3 . Clinical Evaluation of Methods, 33 4 . Evidence-Based Laboratory Medicine, 40 5 . Establishment and Use of Reference Values, 60 6 . Specimen Collection, Processing, and Other Preanalytical Variables, 72 7 . Quality Management, 90 8 . Principles of Basic Techniques and Laboratory Safety, 107 PART II ANALYTICAL TECHNIQUES AND INSTRUMENTATION, 129 9 . Optical Techniques, 129 1 0 . Electrochemistry and Chemical Sensors, 151 1 1 . Electrophoresis, 171 1 2 . Chromatography, 183 1 3 . Mass Spectrometry, 202 1 4 . Enzyme and Rate Analyses, 216 1 5 . Immunochemical Techniques, 236 1 6 . Automation, 254 1 7 . Point-of-Care Instrumentation, 272 PART III ANALYTES, 286 1 8 . Amino Acids, Peptides, and Proteins, 286 1 9 . Serum Enzymes, 318 2 0 . Tumor Markers and Cancer Genes, 337 2 1 . Kidney Function Tests—Creatinine, Urea, and Uric Acid, 364 2 2 . Carbohydrates, 376 2 3 . Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors, 388 2 4 . Electrolytes and Blood Gases, 412 2 5 . Hormones, 430 2 6 . Catecholamines and Serotonin, 442 2 7 . Vitamins, Trace Elements, and Nutritional Assessment, 459 2 8 . Hemoglobin, Iron, and Bilirubin, 499 2 9 . Porphyrins and Porphyrias, 522 3 0 . Therapeutic Drugs and Their Management, 536 3 1 . Clinical Toxicology, 559 3 2 . Toxic Metals, 592 Contents
PART IV PATHOPHYSIOLOGY, 608 3 3 . Diabetes, 608 3 4 . Cardiovascular Disease, 632 3 5 . Kidney Disease, 651 3 6 . Physiology and Disorders of Water, Electrolyte, and Acid-Base Metabolism, 680 3 7 . Liver Disease, 700 3 8 . Gastrointestinal and Pancreatic Diseases, 724 3 9 . Disorders of Bone and Mineral Metabolism, 741 4 0 . Disorders of the Pituitary, 769 4 1 . Disorders of the Adrenal Cortex, 785 4 2 . Thyroid Disorders, 806 4 3 . Reproduction-Related Disorders, 824 4 4 . Pregnancy and Prenatal Testing, 848 4 5 . Newborn Screening and Inborn Errors of Metabolism, 870 4 6 . Pharmacogenetics, 885 PART V MOLECULAR DIAGNOSTICS, 899 4 7 . Principles of Molecular Biology, 899 4 8 . Nucleic Acid Techniques and Applications, 915 4 9 . Genomes and Nucleic Acid Variations, 946 PART VI REFERENCE INFORMATION, 951 5 0 . Reference Information for the Clinical Laboratory, 951
Tietz Fundamentals of CLINICAL CHEMISTRY AND MOLECULAR DIAGNOSTICS
Y ou can now purchase Elsevier products on Evolve! Go to evolve.elsevier.com/html/shop-promo.html to search and browse for products. Activate the complete learning experience that comes with each NEW textbook purchase by registering at Evolve Student Resources for Burtis: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, Seventh Edition, include the following features: Chapter Review Question Answer Key Case Studies http://evolve.elsevier.com/Tietz/fundamentals/ Y O U ’V EJU STPU RCH A SED M O RET H A N AT EX T BO O K ! REGISTER TODA Y!
Tietz Fundamentals of CLINICAL CHEMISTRY AND MOLECULAR DIAGNOSTICS Carl A. Burtis, Ph.D. Emeritus Oak Ridge National Laboratory Oak Ridge, Tennessee Clinical Professor of Pathology University of Utah School of Medicine Salt Lake City, Utah David E. Bruns, M.D. Professor of Pathology University of Virginia School of Medicine Director of Clinical Chemistry and Associate Director of Molecular Diagnostics University of Virginia Health System Charlottesville, Virginia Consulting Editor Barbara G. Sawyer, Ph.D., M.L.S. (A.S.C.P.)CM , MB (A.S.C.P.)CM Professor, Clinical Laboratory Science/ Molecular Pathology Texas Tech University Health Sciences Center Lubbock, Texas Seventh Edition
3251 Riverport Lane St. Louis, Missouri 63043 IE Z FUNDAMEN ALSOF CLINICAL CHEMIS RY , SEVEN H EDI ION ISBN: 978-1-4557-4165-6 Copyright © 2015 by Saunders, an imprint of Elsevier Inc. No part o this publication may be reproduced or transmitted in any orm or by any means, electronic or mechani- cal, including photocopying, recording, or any in ormation storage and retrieval system, without permission in writing rom the publisher. Details on how to seek permission, urther in ormation about the Publisher’ s permis- sions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be ound at our website: www.elsevier.com/permissions. T is book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this f eld are constantly changing. As new research and experience broaden our understanding, changes in research methods, pro essional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any in ormation, methods, compounds, or experiments described herein. In using such in ormation or methods they should be mind ul o their own sa ety and the sa ety o others, including parties or whom they have a pro essional responsibility. With respect to any drug or pharmaceutical products identif ed, readers are advised to check the most current in ormation provided (i) on procedures eatured or (ii) by the manu acturer o each product to be administered, to veri y the recommended dose or ormula, the method and duration o administration, and contraindications. It is the responsibility o practitioners, relying on their own experience and knowledge o their patients, to make diagnoses, to determine dosages and the best treatment or each individual patient, and to take all appropriate sa ety precautions. o the ullest extent o the law, neither the Publisher nor the authors, contributors, or editors, assume any liability or any injury and/or damage to persons or property as a matter o products liability, negligence or otherwise, or rom any use or operation o any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2008, 2001, 1996, 1987, 1976, 1971 ISBN:978-1-4557-4165-6 Content Development Manager: Ellen Wurm-Cutter Content Development Specialist: Andrea Hunolt PublishingServices Manager: Julie Eddy Senior Project Managers: Andrea Campbell, Celeste Clingan Design Direction: Paula Catalano Printed in the United States o America Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication to Seventh Edition Mentor, Colleague, Friend On behal o the worldwide community o clinical laboratorians, we are pleased to dedicate this edition o the Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics to Pro essor Norbert W. ietz, Ph.D. T rough his many scienti c, educational, and editorial ef orts, Pro essor ietz has had a signi cant and worldwide impact on the pro ession, practice, and teachingo clinical laboratory medicine. Pro essor ietz is internationally known or creatingand subsequent editingo one o the rst books produced or clinical laboratorians, the internationally acclaimed Fundamentals of Clinical Chemistry. It was the rst modern textbook that integrated clinical chemistry with the basic medical sciences and pathophysiology. Dr. ietz also edited the rst edition o the Textbook of Clinical Chemistry, a re erence text that bridges the gap between the clinical laboratory and medical management by relatingpathophysiology to analytical results in health and disease. He has also edited the Clinical Guide to Laboratory Tests and the Applied Laboratory Medicine. In summary, Pro essor ietz has been and continues to be a strong advocate o clinical chemistry, and through his energetic scienti ic, educational, and editorial e orts he has encouraged countless clinical chemists, clinical pathologists, and medical technologists to advance their pro ession by linking progress in laboratory medicine with the practice o medicine. he name o ietz is synonymous with the pro ession and practice o quality laboratory medicine. It is our distinct pleasure to dedicate this edition o the Fundamentals of Clinical Chemistry and Molecular Diagnostics to an individual who has had such a signi icant impact on our pro ession and our careers.
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vii T omas M. Annesley, Ph.D. Emeritus Pro essor University o Michigan Medical School Ann Arbor, Michigan; Deputy Editor, Clinical Chemistry Washington, D.C. Mass Spectrometry Fred S. Apple, Ph.D. Medical Director o Clinical Laboratories Hennepin County Medical Center, Pro essor o Laboratory Medicine and Pathology University o Minnesota School o Medicine Minneapolis, Minnesota Cardiovascular Disease Edward R. Ashwood, M.D. Pro essor o Pathology University o Utah School o Medicine; President and Chie Executive O cer ARUP Laboratories Salt Lake City, Utah Clinical Evaluation of Methods Michael N. Badminton, M.B., Ch.B., Ph.D., F.R.C.Path. Honorary Consultant and Clinical Lead, National Acute Porphyria Service (Cardi ) Medical Biochemistry & Immunology University Hospital o Wales; Senior Lecturer Institute o Molecular and Experimental Medicine School o Medicine, Cardi University Heath Park, Cardi Porphyrins and Porphyrias Renze Bais, Ph.D., F.F.Sc. (R.C.P.A.) rbaisconsulting.com Sydney, NSW Australia Enzyme and Rate Analyses; Serum Enzymes James C. Barton, M.D. Director, Southern Iron Disorders Center; Clinical Pro essor o Medicine Department o Medicine University o Alabama at Birmingham Birmingham, Alabama Hemoglobin, Iron, and Bilirubin Lindsay A.L. Bazydlo, Ph.D. Co-Director Clinical Chemistry, University o Florida Health Shands Hospital Director Clinical oxicology, University o Florida Health PathLabs Assistant Pro essor Department o Pathology, Immunology, and Laboratory Medicine University o Florida College o Medicine Gainesville, Florida Electrophoresis Laura K. Bechtel, Ph.D., D.A.B.C.C. Laboratory Director Forensic Laboratories, Inc. Denver, Colorado Clinical oxicology Roger L. Berthol , Ph.D. Pro essor o Pathology Director o Clinical Chemistry, oxicology, and Point o Care esting University o Florida Health Science Center Jacksonville, Florida Disorders of the Pituitary; Disorders of the Adrenal Cortex; T yroid Disorders Patrick M.M. Bossuyt, Ph.D. Pro essor o Clinical Epidemiology Academic Medical Center University o Amsterdam Amsterdam, T e Netherlands Evidence-Based Laboratory Medicine James C. Boyd, M.D. Associate Pro essor o Pathology Chie , Division o Clinical Pathology University o Virginia Medical School Director o Systems Engineering and Core Lab Automation Associate Director o Clinical Chemistry and oxicology University o Virginia Health System Charlottesville, Virginia; Deputy Editor, Clinical Chemistry Washington, D.C. Selection and Analytical Evaluation of Methods—With Statistical echniques; Automation Contributors
Contributors viii David E. Bruns, M.D. Pro essor o Pathology University o Virginia School o Medicine Director o Clinical Chemistry and Associate Director o Molecular Diagnostics University o Virginia Health System Charlottesville, Virginia Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine; Clinical Evaluation of Methods; Evidence-Based Laboratory Medi- cine; Reference Information Carl A. Burtis, Ph.D. Emeritus Oak Ridge National Laboratory Oak Ridge ennessee Clinical Pro essor o Pathology University o Utah School o Medicine Salt Lake City, Utah Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine; Chromatography; Reference Information Daniel W. Chan, Ph.D., D.A.B.C.C., F.A.C.B. Pro essor o Pathology, Oncology, Radiology, and Urology Director o Clinical Chemistry Division Department o Pathology, Director, Center or Biomarker Discovery Johns Hopkins Medical Institutions Baltimore, Maryland umor Markers and Cancer Genes Rossa W.K. Chiu, M.B.B.S, Ph.D., F.R.C.P.A., F.H.K.A.M. (Pathology) Pro essor Department o Chemical Pathology T e Chinese University o Hong Kong Honorary Consultant Department o Chemical Pathology Prince o Wales Hospital Hong Kong, SAR, China Principles of Molecular Biology Allan C. Deacon, Ph.D., F.R.C.Path. Consultant Clinical Scientist Clinical Biochemistry Department Bed ord Hospital Bed ordshire, United Kingdom Porphyrins and Porphyrias Michael P. Delaney, B.Sc., M.D., F.R.C.P. Consultant Nephrologist East Kent Hospitals NHSFoundation rust Canterbury, Kent, United Kingdom Kidney Disease Mari L. DeMarco, Ph.D. Clinical Assistant Pro essor University o British Columbia, Clinical Chemist St. Paul’ s Hospital Department o Pathology and Laboratory Medicine Vancouver, British Columbia, Canada Reproduction-Related Disorders Paul D’Orazio, Ph.D. Director Critical Care Analytical Instrumentation Laboratory Co. Bed ord, Massachusetts Electrochemistry and Chemical Sensors Basil . Doumas, Ph.D. Pro essor Emeritus Department o Pathology Medical College o Wisconsin Milwaukee, Wisconsin Hemoglobin, Iron, and Bilirubin D. Robert Du our, M.D. Consultant, Pathology and Hepatology Veterans A airs Medical Center, Emeritus Pro essor o Pathology George Washington University Medical Center Washington, D.C. Liver Disease John H. Eck eldt, M.D. Vice Chair or Clinical A airs Department o Laboratory Medicine and Pathology University o Minnesota Medical School Minneapolis, Minnesota Hemoglobin, Iron, and Bilirubin Graeme Eisenho er, Ph.D. Pro essor Department o Medicine III Institute o Clinical Chemistry and Laboratory Medicine Chie , Division o Clinical Neurochemistry University Hospital Carl Gustav Carus Dresden at the Dresden University o echnology Dresden, Germany Catecholamines and Serotonin George H. Elder, M.D., F.R.C.P., F.R.C.Path. Emeritus Pro essor Department o Medical Biochemistry and Immunology School o Medicine, Cardi University Cardi , United Kingdom Porphyrins and Porphyrias Jens Peter Goetze, M.D., D.M.Sc. Pro essor, Chie Physician Department o Clinical Biochemistry Rigshospitalet University o Copenhagen and Aarhus Copenhagen, Denmark Cardiovascular Disease David G. Grenache, Ph.D., M. . (A.S.C.P.), D.A.B.C.C., F.A.C.B. Associate Pro essor o Pathology University o Utah School o Medicine Medical Director, Special Chemistry ARUP Laboratories Salt Lake City, Utah Pregnancy and Prenatal esting
Contributors ix Ann M. Gronowski, Ph.D. Pro essor, Department o Pathology and Immunology Pro essor, Department o Obstetrics and Gynecology Washington University School o Medicine St. Louis, Missouri Reproduction-Related Disorders Amy R. Groszbach, M.E.D., M.L. ., M.B. (A.S.C.P.)CM Education Program Coordinator Molecular Genetics Laboratory, Mayo Clinic Program Director, Molecular Genetics echnology Internship Program Mayo School o Health Science Mayo Clinic Rochester, Minnesota Specimen Collection, Processing, and Other Preanalytical Variables Doris M. Haverstick, Ph.D., D.A.B.C.C. Associate Pro essor o Pathology University o Virginia Charlottesville, Virginia Specimen Collection, Processing, and Other Preanalytical Variables Charles D. Hawker, Ph.D., M.B.A., F.A.C.B. Adjunct Pro essor o Pathology University o Utah School o Medicine ARUP Laboratories Salt Lake City, Utah Automation re or Higgins, M.Sc., F.C.A.C.B. Director o Clinical Chemistry GynaLIFEDX Clinical Pro essor Department o Laboratory Medicine and Pathology Faculty o Medicine University o Alberta Edmonton, Alberta Hemoglobin, Iron, and Bilirubin Peter G. Hill, Ph.D., F.R.C.Path. Emeritus Consultant Clinical Biochemistry Royal Derby Hospital Derby, United Kingdom Gastrointestinal and Pancreatic Diseases Christopher P. Holstege, M.D. Chie , Division o Medical oxicology Associate Pro essor, Department o Emergency Medicine and Pediatrics University o Virginia School o Medicine Medical Director, Blue Ridge Poison Center University o Virginia Health System Charlottesville, Virginia Clinical oxicology Gary L. Horowitz, M.D. Associate Pro essor o Pathology Harvard Medical School Director o Clinical Chemistry Beth Israel Deaconess Medical Center Boston, Massachusetts Establishment and Use of Reference Values Glen L. Hortin, M.D., Ph.D. Clinical Pathology Medical Director, Southeast Region Quest Diagnostics ampa, Florida Chromatography; Amino Acids, Peptides, and Proteins Allan S. Jaf e, M.D. Consultant in Cardiology and Laboratory Medicine Pro essor o Medicine Pro essor o Laboratory Medicine and Pathology Chair, CCLSDivision o Laboratory Medicine and Pathology Mayo Clinic and Medical School Rochester, Minnesota Cardiovascular Disease Ishwarlal Jialal, M.D., Ph.D., F.R.C.Path. (London), D.A.B.C.C. Robert E. Stowell Endowed Chair in Experimental Pathology Director o the Laboratory or Atherosclerosis and Metabolic Research Distinguished Pro essor o Pathology and Internal Medicine (Endocrinology, Diabetes, and Metabolism) University o Cali ornia Davis Medical Center Sacramento, Cali ornia Disorders of the Pituitary; Disorders of the Adrenal Cortex George G. Klee, M.D., Ph.D. Emeritus Pro essor o Laboratory Medicine and Pathology College o Medicine Department o Laboratory Medicine and Pathology Mayo Clinic Rochester, Minnesota Quality Management Michael Kleerekoper, M.D., F.A.C.B., F.A.C.P., M.A.C.E. Clinical Pro essor o Internal Medicine/Endocrinology College o Medicine and Li e Sciences University o oledo oledo, Ohio Hormones; Disorders of Bone and Mineral Metabolism Larry J. Kricka, D.Phil, F.A.C.B., C.Chem., F.R.S.C., F.R.C.Path. Pro essor University o Pennsylvania Department o Pathology and Laboratory Medicine Director o General Chemistry and the Critical Care Laboratory Hospital o the University o Pennsylvania Philadelphia, Pennsylvania Optical echniques; Immunochemical echniques Noriko Kusukawa, Ph.D. Director, New echnology Assessment and Licensing ARUP Laboratories Adjunct Associate Pro essor o Pathology University o Utah School o Medicine Salt Lake City, Utah Nucleic Acid echniques and Applications; Genomes and Nucleic Acid Variations Edmund J. Lamb, Ph.D., F.R.C.Path. Head, Department o Clinical Biochemistry East Kent Hospitals NHSFoundation rust Canterbury, Kent, United Kingdom KidneyFunction ests—Creatinine, Urea, and UricAcid;KidneyDisease
Contributors x Geralyn Lambert-Messerlian, Ph.D., F.A.C.B. Pro essor Department o Pathology and Laboratory Medicine Alpert Medical School o Brown University Director Division o Medical Screening and Special esting Women and In ants Hospital Providence, Rhode Island Pregnancy and Prenatal esting James P. Landers, Ph.D. Pro essor o Chemistry Pro essor o Mechanical Engineering University o Virginia Associate Pro essor o Pathology University o Virginia Health System Charlottesville, Virginia Electrophoresis Loralie Langman, Ph.D., F.C.A.C.B., D.A.B.C.C. (C.C., M.B., .C.), D.A.B.F. . Director, oxicology and Drug Monitoring Laboratory Department o Laboratory Medicine and Pathology Mayo Clinic Associate Pro essor o Laboratory Medicine and Pathology Mayo Clinic College o Medicine Rochester, Minnesota Clinical oxicology Vicky A. LeGrys, Ph.D., Dr.A., M. . (A.S.C.P.) C.L.S. (N.C.A.) Pro essor Division o Clinical Laboratory Science School o Medicine University o North Carolina at Chapel Hill Chapel Hill, North Carolina Electrolytes and Blood Gases Kristian Linnet, M.D., Ph.D. Pro essor, Chie , Section o Forensic Chemistry Department o Forensic Medicine Faculty o Health Sciences University o Copenhagen Copenhagen, Denmark Selection and Analytical Evaluation of Methods—With Statistical echniques Stanley F. Lo, Ph.D., D.A.B.C.C., F.A.C.B. Associate Pro essor o Pathology Medical College o Wisconsin Associate Director, Clinical Laboratories Children’ s Hospital o Wisconsin Milwaukee, Wisconsin Principles of Basic echniques and Laboratory Safety Y.M. Dennis Lo, M.A., D.M., D.Phil., F.R.C.P., F.R.C.Path., F.R.S. Li Ks Shing Pro essor o Medicine Pro essor o Chemical Pathology Department o Chemical Pathology T e Chinese University o Hong Kong Prince o Wales Hospital Hong Kong S.A.R., China Principles of Molecular Biology Nicola Longo, M.D., Ph.D., F.A.C.M.G. Pro essor o Pediatrics and Pathology Chie , Division o Medical Genetics Department o Pediatrics, Medical Co-Director, ARUP Biochemical Genetics Laboratory, University o Utah Salt Lake City, Utah Newborn Screening and Inborn Errors of Metabolism Gwendolyn A. McMillin, Ph.D., D.A.B.C.C. (C.C., .C.) Assistant Pro essor (Clinical) o Pathology University o Utah School o Medicine Medical Director, oxicology, race Elements, Pharmacogenomics ARUP Laboratories Salt Lake City, Utah T erapeutic Drugs and T eir Management; Pharmacogenetics; Refer- ence Information Mark E. Meyerhof , Ph.D. Philip J. Elving Pro essor o Chemistry Department o Chemistry T e University o Michigan Ann Arbor, Michigan Electrochemistry and Chemical Sensors T omas P. Moyer, Ph.D. Pro essor o Laboratory Medicine Department o Laboratory Medicine & Pathology Mayo College o Medicine Mayo Clinic Rochester, Minnesota oxic Metals Mauro Panteghini, M.D. Pro essor o Clinical Biochemistry and Clinical Molecular Biology Department o Biomedical and Clinical Sciences “Luigi Sacco” University o Milan Director, Clinical Pathology Laboratory Ospedale “Luigi Sacco” Milan, Italy Enzyme and Rate Analyses; Serum Enzymes Jason Y. Park, M.D., Ph.D., F.C.A.P. Assistant Pro essor Department o Pathology University o exas Southwestern Medical Center Director Advanced Diagnostics Laboratory Children’ s Medical Center Dallas, exas Optical echniques; Immunochemical echniques Marzia Pasquali, Ph.D., F.A.C.M.G. Pro essor o Pathology University o Utah School o Medicine Medical Director, Biochemical Genetics and Supplemental Newborn Screening ARUP Laboratories Salt Lake City, Utah Newborn Screening and Inborn Errors of Metabolism
Contributors xi Christopher P. Price, Ph.D., F.R.S.C., F.R.C.Path. Visiting Pro essor in Clinical Biochemistry Department o Primary Care Health Sciences University o Ox ord Ox ord, United Kingdom Evidence-Based Laboratory Medicine; Point-of-Care Instrumentation; Kidney Function ests—Creatinine, Urea, and Uric Acid; Kidney Disease Alex J. Rai, Ph.D., D.A.B.C.C., F.A.C.B. Director, Special Chemistry Laboratory New Y ork Presbyterian Hospital Associate Pro essor o Pathology and Cell Biology Chie Scientif c O cer, Center or Advanced Laboratory Medicine Department o Pathology and Cell Biology Columbia University Medical Center New Y ork, New Y ork umor Markers and Cancer Genes Alan . Remaley, M.D., Ph.D. Department o Laboratory Medicine National Institutes o Health Bethesda, Maryland Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors Nader Ri ai, Ph.D. T e Louis Joseph Gay-Lussac Chair in Laboratory Medicine Director o Clinical Chemistry Boston Children’ s Hospital Pro essor o Pathology Harvard Medical School Boston, Massachusetts Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors Juha Risteli, M.D, Ph.D., F.E.B.M.B. Pro essor o Clinical Chemistry Department o Clinical Chemistry Institute o Diagnostics University o Oulu Oulu, Finland Disorders of Bone and Mineral Metabolism Leila Risteli, M.D., Ph.D., M.A., F.E.B.M.B. Chie Physician Northern Finland Laboratory Centre (NordLab) Adjunct Pro essor o Medical Biochemistry University o Oulu Oulu, Finland Adjunct Pro essor o Clinical Chemistry University o ampere ampere, Finland Disorders of Bone and Mineral Metabolism Norman B. Roberts, M.Sc., Ph.D., C.Chem. Consultant Clinical Scientist Department o Clinical Biochemistry T e Royal Liverpool and Broadgreen University Hospitals Honorary Reader, Clinical Chemistry T e University o Liverpool Liverpool, United Kingdom Vitamins, race Elements, and Nutritional Assessment Alan L. Rockwood, Ph.D., D.A.B.C.C. Scientif c Director or Mass Spectrometry ARUP Laboratories Pro essor (Clinical) o Pathology University o Utah School o Medicine Salt Lake City, Utah Mass Spectrometry T omas G. Rosano, Ph.D., D.A.B.F. ., D.A.B.C.C. Head o Clinical Laboratory Services Director o Clinical Chemistry and Forensic oxicology Albany Medical Center Hospital and College Albany, New Y ork Catecholamines and Serotonin Francois A. Rousseau, M.D., M.S., F.R.C.P.C. Head, Department o Medical Biology Faculty o Medicine University o Laval Quebec, Canada Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine David B. Sacks, M.D., Ch.B., F.R.C.Path. Adjunct Pro essor Department o Medicine Division o Endocrinology and Metabolism Georgetown University Washington, D.C. Carbohydrates; Diabetes Desmond Schatz, M.D. Pro essor and Associate Chairman Department o Pediatrics Division o Endocrinology Medical Director, Diabetes Center University o Florida Gainesville, Florida T yroid Disorders Emily I. Schindler, M.D., Ph.D. Resident Physician Department o Pathology and Immunology Barnes Jewish Hospital St. Louis, Missouri Electrolytes and Blood Gases; Physiology and Disorders of Water, Electrolyte, and Acid-Base Metabolism Mitchell G. Scott, Ph.D. Pro essor o Pathology and Immunology Co-Medical Director, Clinical Chemistry Division o Laboratory and Genomic Medicine Washington University School o Medicine St. Louis, Missouri Electrolytes and Blood Gases; Physiology and Disorders of Water, Electrolyte, and Acid-Base Metabolism Alan Shenkin, Ph.D., F.R.C.P., F.R.C.Path. Emeritus Pro essor Unit o Clinical Chemistry School o Clinical Sciences University o Liverpool Liverpool, United Kingdom Vitamins, race Elements, and Nutritional Assessment
Contributors xii Nicholas E. Sherman, Ph.D. Research Associate Pro essor Director o Mass Spectrometry University o Virginia Charlottesville, Virginia Mass Spectrometry Christine L.H. Snozek, Ph.D., D.A.B.C.C. Assistant Pro essor Mayo Clinic College o Medicine Director o Chemistry, Collections/Processing, and Point-o -Care esting Department o Laboratory Medicine and Pathology Mayo Clinic in Arizona Scottsdale, Arizona T erapeutic Drugs and T eir Management Lori J. Sokoll, Ph.D., F.A.C.B. Associate Pro essor o Pathology, Oncology, and Urology Associate Director, Clinical Chemistry Division Department o Pathology Johns Hopkins Medical Institutions Baltimore, Maryland umor Markers and Cancer Genes Andrew St. John, Ph.D. ARC Consulting Mt. Lawley Western Australia, Australia Point-of-Care Instrumentation G. Russell Warnick, M.S., M.B.A. Executive Director Foundation or Health In ormation and echnology Chie Science O cer Health Diagnostic Laboratory Richmond, Virginia Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors James O. Westgard, Ph.D. Pro essor Department o Pathology and Laboratory Medicine University o Wisconsin Medical School Madison, Wisconsin Quality Management Sharon D. Whatley, Ph.D. Clinical Biochemist Medical Biochemistry Department University Hospital o Wales, Cardi , United Kingdom Porphyrins and Porphyrias Ronald J. Whitley, Ph.D., F.A.C.B., D.A.B.C.C. Pro essor Department o Pathology and Laboratory Medicine University o Kentucky Director o Clinical Chemistry, oxicology, and Core Laboratories University o Kentucky Medical Center College o Medicine Lexington, Kentucky Catecholamines and Serotonin William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P. Pro essor Departments o Pathology, Immunology & Laboratory Medicine, Pediatrics, and Molecular Genetics & Microbiology Principle Investigator, ype 1 Diabetes rialNet ICA Core Laboratory Director, UF Pathology Laboratories, Endocrine Autoantibody Laboratory University o Florida Gainesville, Florida Disorders of Bone and Mineral Metabolism; Disorders of the Pituitary; Disorders of the Adrenal Cortex; T yroid Disorders Carl . Wittwer, M.D., Ph.D. Pro essor o Pathology University o Utah School o Medicine Salt Lake City, Utah Nucleic Acid echniques and Applications; Genomes and Nucleic Acid Variations
xiii As a practitioner and instructor o clinical chemistry or over 20 years, I have observed many innovative changes in the clinical laboratory, rom implementation o new analytical techniques to dependence on laboratory in ormatics to the inclusion o molecular testing and its unique practice stan- dards. I have worked with the editors and publishers o Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics as consulting editor or three editions and have ollowed each edition as they re ect the numerous advances in laboratory science. In the area o education, such updates are crucial or in orming students o what they should expect in their careers as pro essional laboratorians or as other practitioners in health care. As with previous editions, the seventh edition o Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics presents in ormation that today’ s clinical chemistry students and practicing laboratorians must know to succeed in this dis- cipline and in the contemporary world o pathology. T e true purpose o education must go beyond providing the knowledge necessary to be success ul in a particular eld. It must also stimulate and encourage students to investigate knowledge beyond that presented in the ormal classroom set- ting.T e highlyregarded authors o the seventh edition o Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics excel at presenting essential knowledge. T eir updates and re- visions o traditional topics and the addition o new chapters, such as “Pharmacogenetics” and “Genomes and Nucleic Acid Alterations,” provide interesting and indispensable material or the active learner. o inspire students to seek in ormation be- yond that provided in the various chapters, the seventh edition provides end-o -chapter multiple-choice questions that en- courage continued review and study. Updated websites within each chapter of er urther sources o data to increase under- standing o the subject matter. T ought-provoking gures that illustrate chapter concepts and innovative algorithms that pro- vide a unique way o examining diagnostic issues have been added to this edition. For both the educator and the student, improved and testable objectives have been designed and related est Bank questions have been added, revised, or modi ed. For the laboratory science student, the pro essional laboratorian, and the practicing pathologist, this textbook serves as an outstand- ing resource or (1) the study o basic laboratory operations, (2) understanding clinical chemistry analytes, and (3) com- prehending undamental pathophysiology. T e last chapter “Re erence In ormation or the Clinical Laboratory” provides an excellent source o re erence intervals or analytes o clini- cal relevance. As with previous editions o Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, this textbook provides something o interest or anyone who is involved in the eld o medical laboratory science. It is a privilege and an honor to have been invited to take part in the continuation o such a quality endeavor as this ex- ceptional textbook. o observe and comment on its continued growth and maturation is both rewarding and stimulating. I nd it truly ul lling to know that students, educators, manag- ers, and pathologists use this text as a primary resource in the classroom, laboratory, and clinic or in ormation regardingthe eld o clinical chemistry. Maintaining the highest standards o quality while providing crucial contemporary in ormation that is both concise and readable, this volume continues in the tradition o excellence set by previous editions o Tietz Funda- mentals of Clinical Chemistry and Molecular Diagnostics. Barbara G. Sawyer, Ph.D., M.L.S.(A.S.C.P.)CM , M.B.(A.S.C.P.)CM Professor, Clinical Laboratory Science/Molecular Pathology Foreword
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xv As the discipline o clinical laboratory science and medi- cine has evolved and expanded, each new edition o Tietz Fundamentals of Clinical Chemistry has been revised to re ect these changes. T e seventh edition o this series is no excep- tion, as we have made signi cant revisions in its ormat and content. First, re ecting the e ect that molecular diagnos- tics has had and continues to have on the practice o clinical chemistry and laboratory medicine, we have retitled the seventh edition as Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics. Consequently, chapters have been added on the topic o molecular diagnostics and many o the other updated chapters now include discussions o genetic testing and descriptions o the genetic basis o diseases. Second, 47 new authors along with 53 veterans rom the sixth edition have joined our company o subject-matter experts to revise and produce chapters that re ect the state- o -the-art in their respective elds. Consequently, this new edition covers many new topics and updates in ormation on older ones. With these changes, the seventh edition now contains 50 chapters that are grouped into sections entitled (I) Principleso LaboratoryMedicine,(II) Analytical echniques and Instrumentation, (III) Analytes, (IV) Pathophysiology, (V) Molecular Diagnostics, and (VI) Re erence In ormation. T ird, learning tools have been added or expanded. For ex- ample, a set o objectives and a list o keyterms and de nitions were included at the beginning o each chapter. (Note: in each chapter key terms are listed in alphabetical order in a bold red ont and again when each appears or the rst time in their respective chapter.) At the end o each chapter, a list o review questions has been added to assist students in the review o the salient points covered in each chapter. At the end o the book, we have combined the keywords and de nitions into a Glossary. O note, many o these key words and de nitions were obtained, in whole or in part, rom the 32nd edition o Dorland’ s Illustrated Medical Dictionary, with permission kindly granted by Elsevier. As with the sixth edition, we have relied on in ormation technology to prepare and produce the seventh edition. For example, each chapter was submitted and edited via Elsevier’ s “Electronic Manuscript Submission System.” In addition, many o the gures, especially those that included chemi- cal structures, were drawn or revised by Ed Ashwood using ChemWindows sof ware. T is resulted in a uni orm represen- tation o chemical structures and acilitated the integration o gures within the text while reducing errors. Readers will note that re erences to web-based sources o in ormation are ound throughout the text. o assist us in preparing the seventh edition, we again in- vited Barbara G. Sawyer, Ph.D., to join our editorial team as an educational consultant. Because o her experience with using Fundamentalsas a teaching text and her perspective as an edu- cator, Pro essor Sawyer’ s advice and assistance were again very use ul to us as we produced the seventh edition. We appreciate the opportunity provided us by Elsevier to prepare the seventh edition o Tietz Fundamentals of Clinical Chemistry. It has been an exciting, challenging, and educa- tional experience. We trust that this edition will live up to the reputation and success o its distinguished predecessors. We have enjoyed working with the team o dedicated authors that have spent many hours preparing comprehensive chapters that are authoritative and timely. We thank them sincerely and believe that they have enabled us to produce a textbook that is re ective o the diverse, technical, and practical nature o the current practice o clinical laboratory science and medicine. We have also bene ted rom and enjoyed working with the Elsevier sta , especially Sonya Seiga use, Executive Content Strategist;Ellen Wurm-Cutter, Content Development Manager; and Rachel E. McMullen and Andrea Campbell, Senior Project Managers.T eir patience, cooperation,advice,and pro essional dedication are grate ully acknowledged. Finally, we thank our valued colleague Ed Ashwood or his years o work as an editor o this book’ s predecessors. T e cur- rent product continues to bene t rom his manycontributions. Carl A. Burtis David E. Bruns Preface
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xvii P AR T I PRINCIPLES OF LABORATORY MEDICINE 1 Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine, 1 David E. Bruns, M.D., François A. Rousseau, M.D., and Carl A. Burtis, Ph.D. Laboratory Medicine, 1 Clinical Chemistry and Laboratory Medicine, 2 Molecular Diagnostics, 3 Ethical Issues in Laboratory Medicine, 3 Review Questions, 5 2 Selection and Analytical Evaluation of Meth- ods—With Statistical Techniques, 6 Kristian Linnet, M.D., Ph.D. and James C. Boyd, M.D. Method Selection, 7 Basic Statistics, 8 Basic Concepts in Relation to Analytical Methods, 11 Analytical Goals, 15 Method Comparison, 16 Monitoring Serial Results, 28 Traceability and Measurement Uncertainty, 28 So tware Packages, 30 Review Questions, 31 3 Clinical Evaluation of Methods, 33 Edward R. Ashwood, M.D. and David E. Bruns, M.D. Sensitivity and Speci city, 33 Receiver Operating Characteristic Plots, 34 Probabilistic Reasoning, 35 Prevalence, 35 Predictive Values, 35 Odds Ratio, 36 Likelihood Ratio, 36 Bayes’ Theorem, 36 Combination Testing, 37 Methods o Assessing Diagnostic Accuracy, 38 Review Questions, 38 4 Evidence-Based Laboratory Medicine, 40 Christopher P. Price, Ph.D., F.R.S.C., F.R.C.Path. Patrick M.M. Bossuyt, Ph.D., and David E. Bruns, M.D. Evidence-Based Medicine—What Is It?, 41 Evidence-Based Medicine and Laboratory Medicine, 42 In ormation Needs in Evidence-Based Laboratory Medicine, 43 Characterization o Diagnostic Accuracy Tests, 44 Outcomes Studies, 45 Systematic Reviews o Diagnostic Tests, 48 Economic Evaluations o Diagnostic Testing, 50 Clinical Practice Guidelines, 53 Clinical Audit, 56 Applying the Principles o Evidence-Based Laboratory Medicine in Routine Practice, 57 Review Questions, 58 5 Establishment and Use of Reference Values, 60 Gary L. Horowitz, M.D. Establishment o Re erence Values, 61 Use o Re erence Values, 67 Review Questions, 70 6 Specimen Collection, Processing, and Other Preanalytical Variables, 72 Doris M. Haverstick, Ph.D., D.A.B.C.C., and Amy R. Groszbach, M.E.D., M.L. ., M.B.(A.S.C.P.)CM Types o Specimens, 73 Handling o Specimens or Analysis, 81 Review Questions, 88 7 Quality Management, 90 George G. Klee, M.D., Ph.D. and JamesO. Westgard, Ph.D. Fundamentals o Total Quality Management, 91 Implementing TQM, 93 Personnel Competency and Training, 94 The Total Testing Process, 94 Control o Preanalytical Variables, 95 Control o Analytical Variables, 96 External Quality Assessment and Pro ciency Testing Programs, 102 Contents
Contents xviii New Quality Initiatives, 103 Review Questions, 105 8 Principles of Basic Techniques and Laboratory Safety, 107 Stanley F. Lo, Ph.D., D.A.B.C.C., F.A.C.B. Concept o Solute and Solvent, 108 Units o Measurement, 109 Chemicals, 111 Re erence Materials, 112 Basic Techniques and Procedures, 113 Review Questions, 127 P A R T II ANALYTICAL TECHNIQUES AND INSTRUMENTATION 9 Optical Techniques, 129 L.J. Kricka, D.Phil., F.A.C.B., C.Chem., F.R.S.C., F.R.C.Path. and Jason Y . Park, M.D., Ph.D., F.C.A.P. Photometry and Spectrophotometry, 131 Instrumentation, 133 Ref ectance Photometry, 138 Atomic Absorption Spectrophotometry, 138 Fluorometry, 139 Phosphorimetry, 146 Luminometry, 146 Nephelometry and Turbidimetry, 147 Review Questions, 149 10 Electrochemistry and Chemical Sensors, 151 Paul D’Orazio, Ph.D. and Mark E. Meyerhof , Ph.D. Potentiometry, 152 Voltammetry/Amperometry, 158 Conductometry, 162 Coulometry, 163 Optical Chemical Sensors, 163 Biosensors, 164 Review Questions, 169 11 Electrophoresis, 171 Lindsay A.L. Bazydlo, Ph.D. and James P. Landers, Ph.D. Basic Concepts and De nitions, 172 Theory o Electrophoresis, 172 Description o Technique, 172 Types o Electrophoresis, 175 Technical Considerations, 180 Review Questions, 181 12 Chromatography, 183 Glen L. Hortin, M.D., Ph.D. and Carl A. Burtis, Ph.D. Basic Concepts, 184 Separation Mechanisms, 187 Planar Chromatography, 189 Column Chromatography, 190 Qualitative and Quantitative Analyses, 198 Review Questions, 200 13 Mass Spectrometry, 202 Alan L. Rockwood, Ph.D., D.A.B.C.C., T omas M. Annesley, Ph.D., and Nicholas E. Sherman, Ph.D. Basic Concepts and De nitions, 203 Instrumentation, 205 Clinical Applications, 213 Review Questions, 214 14 Enzyme and Rate Analyses, 216 Renze Bais, Ph.D., F.F.Sc. (R.C.P.A.) and Mauro Pan- teghini, M.D. Basic Principles, 217 Enzyme Kinetics, 223 Analytical Enzymology, 229 Review Questions, 234 15 Immunochemical Techniques, 236 L.J. Kricka, D.Phil., F.A.C.B., C.Chem., F.R.S.C., F.R.C.Path. and J.Y . Park, M.D., Ph.D., F.C.A.P. Basic Concepts and De nitions, 237 Antigen-Antibody Binding, 238 Qualitative Methods, 240 Quantitative Methods, 242 Other Immunochemical Techniques, 252 Review Questions, 252 16 Automation, 254 James C. Boyd, M.D. and Charles D. Hawker, Ph.D., M.B.A., F.A.C.B. Basic Concepts, 255 Automation o Analytical Processes, 255 Integrated Automation or the Clinical Labora- tory, 263 Practical Considerations, 267 Other Areas o Automation, 269 Review Questions, 270 17 Point-of-Care Instrumentation, 272 Christopher P. Price, Ph.D., F.R.S.C., F.R.C.Path. and Andrew St. John, Ph.D., F.F.Sc. (R.C.P.A.) Analytical and Technological Considerations, 273 Implementation and Management Consider- ations, 280 Review Questions, 284 P A R T III ANALYTES 18 Amino Acids, Peptides, and Proteins, 286 Glen L. Hortin, M.D., Ph.D. Amino Acids, 287 Peptides and Proteins, 292 Analysis o Proteins, 293 Plasma and Serum Proteins, 299 Review Questions, 317
Contents xix 19 Serum Enzymes, 318 Mauro Panteghini, M.D. and Renze Bais, Ph.D., F.F.Sc. (R.C.P.A.) Basic Concepts, 319 Muscle Enzymes, 319 Liver Enzymes, 322 Pancreatic Enzymes, 328 Other Clinically Important Enzymes, 331 Enzymes as Cardiovascular Risk Markers, 334 Review Questions, 335 20 Tumor Markers and Cancer Genes, 337 Lori J. Sokoll, Ph.D., F.A.C.B., Alex J. Rai, Ph.D., D.A.B.C.C., F.A.C.B., and Daniel W. Chan, Ph.D., D.A.B.C.C., F.A.C.B. Cancer, 339 Clinical Applications, 339 Evaluating Clinical Utility, 341 Clinical Guidelines, 342 Analytical Methods, 342 Enzymes, 342 Hormones, 347 Onco etal Antigens, 349 Cytokeratins, 351 Carbohydrate Markers, 352 Blood Group Antigens, 354 Proteins, 355 Receptors, 357 Circulating Tumor, 358 Genetic and Molecular Markers, 358 Other Molecular Tests, 362 Microarray-Based Markers, 362 Review Questions, 363 21 Kidney Function Tests—Creatinine, Urea, and Uric Acid, 364 Edmund J. Lamb, Ph.D., F.R.C.Path. and Christopher P. Price, Ph.D., F.R.C.Path. Creatinine, 365 Urea, 368 Uric Acid, 370 Review Questions, 374 22 Carbohydrates, 376 David B. Sacks, M.D., Ch.B., F.R.C.Path. Chemistry o Carbohydrates, 377 Biochemistry and Physiology, 379 Analytical Methodology, 382 Review Questions, 387 23 Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors, 388 Alan . Remaley, M.D., Ph.D., Nader Ri ai, Ph.D., and G. Russell Warnick, M.S., M.B.A. Basic Lipids, 389 Lipoproteins, 397 Apolipoproteins, 399 Metabolism o Lipoproteins, 399 Clinical Signi cance, 401 Analysis o Lipids, Lipoproteins, and Apolipo- proteins, 407 Advanced Testing or Risk o Cardiovascular Disease, 409 Review Questions, 410 24 Electrolytes and Blood Gases, 412 Mitchell G. Scott, Ph.D., Vicky A. LeGrys, Ph.D., Dr.A., M. .(A.S.C.P.), C.L.S.(N.C.A.), and Emily I. Schindler, M.D., Ph.D. Electrolytes, 413 Principles o Osmotic Pressure and Osmosis, 420 Blood Gases and pH, 421 Review Questions, 428 25 Hormones, 430 Michael Kleerekoper, M.D., F.A.C.B., F.A.C.P., M.A.C.E. Classi cation, 431 Release and Action o Hormones, 435 Role o Hormone Receptors, 436 Postreceptor Actions o Hormones, 437 Measurements o Hormones and Related Ana- lytes, 439 Review Questions, 441 26 Catecholamines and Serotonin, 442 Graeme Eisenho er, Ph.D., T omas G. Rosano, Ph.D., D.A.B.F. ., D.A.B.C.C., and Ronald J. Whitley, Ph.D., F.A.C.B., D.A.B.C.C. Chemistry, Biosynthesis, Release, and Me- tabolism, 444 Physiology o Catecholamine and Serotonin Systems, 446 Clinical Applications, 449 Analytical Methodology, 453 Review Questions, 458 27 Vitamins, Trace Elements, and Nutritional As- sessment, 459 Alan Shenkin, Ph.D., F.R.C.P., F.R.C.Path. and Norman B. Roberts, M.Sc., Ph.D., C.Chem. Vitamins, 461 Trace Elements, 482 Review Questions, 498 28 Hemoglobin, Iron, and Bilirubin, 499 re or Higgins, M.Sc., F.C.A.C.B., John H. Eck eldt, M.D., Ph.D., James C. Barton, M.D., and Basil . Doumas, Ph.D. Hemoglobin, 501 Iron, 508 Bilirubin, 513 Review Questions, 519
Contents xx 29 Porphyrins and Porphyrias, 522 Michael N. Badminton, M.B.Ch.B., Ph.D., F.R.C.Path., Sharon D. Whatley, Ph.D., Allan C. Deacon, Ph.D., F.R.C.Path., and George H. Elder, M.D., F.R.C.P., F.R.C.Path. Porphyrin and Heme Chemistry, 523 Primary Porphyrin Disorders, 527 Abnormalities o Porphyrin Metabolism not Caused by Porphyria, 529 Laboratory Diagnosis o Porphyria, 530 Analytical Methods, 533 Review Questions, 534 30 Therapeutic Drugs and Their Management, 536 Christine L.H. Snozek, Ph.D., D.A.B.C.C. and Gwendo- lyn A. McMillin, Ph.D., D.A.B.C.C.(C.C., .C.) Basic Concepts, 537 Clinical and Analytical Considerations, 543 Speci c Drug Groups, 545 Review Questions, 558 31 Clinical Toxicology, 559 Loralie Langman, Ph.D., F.C.A.C.B., D.A.B.C.C.(C.C., M.B., .C.), D.A.B.F. ., Laura K. Bechtel, Ph.D., D.A.B.C.C., and Christopher P. Holstege, M.D. Basic In ormation, 561 Screening Procedures or Detection o Drugs, 562 Pharmacology and Analysis o Speci c Drugs and Toxic Agents, 564 Agents That Cause Cellular Hypoxia, 565 Alcohols, 566 Analgesics (Nonprescription), 569 Agents Related to Anticholinergic Toxidrome, 570 Agents Related to Cholinergic Toxidrome, 572 Drugs o Abuse, 574 Drugs Used in Sexual Assault, 586 Review Questions, 590 32 Toxic Metals, 592 T omas P. Moyer, Ph.D. Assessment o Metal Poisoning, 593 Speci c Metals, 594 Review Questions, 606 PART IV PATHOPHYSIOLOGY 33 Diabetes, 608 David B. Sacks, M.B., Ch.B., F.R.C.Path. Classi cation, 610 Hormones that Regulate Blood Glucose Concentration, 611 Measurement o Insulin, Proinsulin, C-Peptide, and Glucagon, 614 Pathogenesis o Type 1 Diabetes Mellitus, 616 Pathogenesis o Type 2 Diabetes Mellitus, 617 Diagnosis o Diabetes, 618 Chronic Complications o Diabetes Mellitus, 620 Role o the Clinical Laboratory in Diabetes Mellitus, 620 Sel -Monitoring o Blood Glucose, 621 Alternatives to Meters or Monitoring o Blood Glucose, 623 Ketone Bodies, 623 Glycated Proteins, 625 Urinary Albumin Excretion, 629 Review Questions, 630 34 Cardiovascular Disease, 632 Fred S. Apple, Ph.D., Jens Peter Goetze, M.D., D.M.Sc., and Allan S. Jaf e, M.D. Anatomy and Physiology o the Heart, 633 Cardiac Disease, 635 Cardiac Biomarkers, 638 Review Questions, 649 35 Kidney Disease, 651 Michael P. Delaney, B.Sc., M.D., F.R.C.P., Christopher P. Price, Ph.D., F.R.S.C., F.R.C.Path. and Edmund J. Lamb, Ph.D., F.R.C.Path. Anatomy, 653 Kidney Function, 655 Kidney Physiology, 658 Pathophysiology o Kidney Disease, 663 Other Diseases o the Kidney, 671 Renal Replacement Therapy, 675 Review Questions, 678 36 Physiology and Disorders of Water, Electrolyte, and Acid-Base Metabolism, 680 Emily I. Schindler, M.D., Ph.D. and Mitchell G. Scott, Ph.D. Total Body Water—Volume and Distribution, 681 Electrolytes, 682 Acid-Base Physiology, 688 Conditions Associated with Abnormal Acid-Base Status and Abnormal Electrolyte Composition o the Blood, 692 Review Questions, 698 37 Liver Disease, 700 D. Robert Du our, M.D. Anatomy o the Liver, 702 Biochemical Functions o the Liver, 704 Clinical Mani estations o Liver Disease, 707 Diseases o the Liver, 710 Diagnostic Strategy, 720 Review Questions, 722
Contents xxi 38 Gastrointestinal and Pancreatic Diseases, 724 Peter G. Hill, Ph.D., F.R.C.Path. Anatomy, 725 The Digestive Process, 726 Gastrointestinal Regulatory Peptides, 728 Stomach, Intestinal, and Pancreatic Diseases and Disorders, 730 Review Questions, 740 39 Disorders of Bone and Mineral Metabolism, 741 Juha Risteli, M.D., Ph.D., F.E.B.M.B., William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P., Michael Kleerekoper, M.D., F.A.C.B., F.A.C.P., M.A.C.E., and Leila Risteli, M.D., Ph.D., M.A., F.E.B.M.B. Overview o Bone and Mineral Metabolism, 743 Calcium, 744 Phosphate, 749 Magnesium, 751 Hormones Regulating Mineral Metabolism, 753 Integrated Control o Mineral Metabolism, 760 Biochemical Markers o Bone Turnover, 761 Metabolic Bone Diseases, 765 Review Questions, 767 40 Disorders of the Pituitary, 769 Ishwarlal Jialal, M.D., Ph.D., F.R.C.Path.(London), D.A.B.C.C., William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P., and Roger L. Berthol , Ph.D. Hypothalamic Regulation, 772 Hormones o the Adenohypophysis, 772 Hormones o the Neurohypophysis, 779 Assessment o Anterior Pituitary Lobe Reserve, 782 Review Questions, 783 41 Disorders of the Adrenal Cortex, 785 Roger L. Berthol , Ph.D., Ishwarlal Jialal, M.D., Ph.D., F.R.C.Path.(London), D.A.B.C.C., and William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P. General Steroid Chemistry, 786 Adrenocortical Steroids, 788 Dynamic Tests o Adrenal Function, 793 Disorders o the Adrenal Cortex, 795 Laboratory Evaluation o Adrenocortical Function, 800 Review Questions, 805 42 Thyroid Disorders, 806 William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P., Desmond Schatz, M.D., and Roger L. Berthol , Ph.D. Thyroid Hormones, 808 Thyroid Disorders, 812 Analytical Methodology, 818 Review Questions, 822 43 Reproduction-Related Disorders, 824 Mari L. DeMarco, Ph.D. and Ann M. Gronowski, Ph.D. Male Reproductive Biology, 826 Female Reproductive Biology, 830 In ertility, 841 Analytical Methodology, 843 Review Questions, 846 44 Pregnancy and Prenatal Testing, 848 David G. Grenache, Ph.D., M. . (A.S.C.P.), D.A.B.C.C., F.A.C.B. and Geralyn Lambert-Messerlian, Ph.D., F.A.C.B. Human Pregnancy, 850 Maternal Adaptation, 853 Functional Development o the Fetus, 854 Maternal and Fetal Health Assessment, 855 Complications o Pregnancy, 856 Prenatal Screening or Fetal De ects, 859 Analytical Methodology, 863 Review Questions, 868 45 Newborn Screening and Inborn Errors of Metabolism, 870 Marzia Pasquali, Ph.D., F.A.C.M.G. and Nicola Longo, M.D., Ph.D., F.A.C.M.G. Inheritance Pattern o Metabolic Disorders, 872 Newborn Screening, 872 Inborn Errors o Metabolism, 873 Diagnostic Tests or Inherited Disorders o Metabolism, 882 Review Questions, 883 46 Pharmacogenetics, 885 Gwendolyn A. McMillin, Ph.D., D.A.B.C.C. (C.C., .C.) De ning Pharmacogenetic Targets, 887 Approaches to Pharmacogenetic Testing, 887 Clinical Applications o Pharmacogenetic Test- ing, 888 Drug Metabolism and Pharmacogenomics, 889 Review Questions, 897 P A R T V MOLECULAR DIAGNOSTICS 47 Principles of Molecular Biology, 899 Y . M. Dennis Lo, M.A., D.M., D.Phil., F.R.C.P., F.R.C.Path., F.R.S. and Rossa W. K. Chiu, M.B.B.S., Ph.D., F.R.C.P.A., F.H.K.A.M. (Pathology) Landmark Developments in Genetics and Molecular Diagnostics, 901 The Essentials, 902 Nucleic Acid Structure and Organization, 902 Nucleic Acid Physiology and Functional Regu- lation, 906 Genetics and Epigenetics, 909 Beyond the Nuclear Genome, 911 Understanding Our Genome, 912 Review Questions, 913
Contents xxii 48 Nucleic Acid Techniques and Applications, 915 Carl . Wittwer, M.D., Ph.D. and Noriko Kusukawa, Ph.D. Nucleic Acid Enzymes, 918 Ampli cation Techniques, 919 Detection Techniques, 924 Discrimination Techniques, 924 Review Questions, 944 49 Genomes and Nucleic Acid Variations, 946 Carl . Wittwer, M.D., Ph.D. and Noriko Kusukawa, Ph.D. Genomes and Nucleic Acid Variations, 947 Review Questions, 960 P A R T VI REFERENCE INFORMATION 50 Reference Information for the Clinical Labora- tory, 951 Gwendolyn A. McMillin, Ph.D., D.A.B.C.C. (C.C., .C.), Carl A. Burtis, Ph.D., and David E. Bruns, M.D. Re erence Intervals and Values, 952 Therapeutic and Toxic Levels o Drugs, 982 Critical Values, 993
1 P A R T I Principles of Laboratory Medicine C H A P TE R 1 Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine David E. Bruns, M.D., Francois A. Rousseau, M.D., and Carl A. Burtis, Ph.D. Ob je c tive s 1. De ne the ollowing terms: Core laboratory Molecular diagnostics Ethics Pharmacogenetics Laboratorymedicine 2. List and explain sixreasons or per orming a laboratorytest. 3. Describe the eld o laboratory medicine, including subdisci- plines, in ormation handling, and ethical issues. 4. State the contribution o epidemiology to the eld o clinical chemistry. 5. State the applications o molecular diagnostics in laboratory medicine. 6. List and explain ve ethical issues that con ront laboratorians; state the criticalimportance o maintaining con dentialityin the laboratory. 7. Evaluate a possible con dentiality or confict o interest issue and determine whether it is an ethics violation. Ke y Wo rd s a n d De fin itio n s Core laboratory Alaboratory that provides all o the high-volume and emergencytesting in manyhospitals. Ethics Rules or standards governing the conduct o an individual or the members o a pro ession. Laboratory medicine Acomponent o laboratory science that is involved in the selection, provision, and interpretation o diag- nostic testing o individual specimens. Laboratory testing A process conducted in a clinical laboratory to rule in or rule out a diagnosis, to select and monitor disease treatment, to provide a prognosis, to screen or a disease, or to determine the severityo andmonitora physiologicaldisturbance. Molecular diagnostics U se o molecular biologytechniques or the purposes o prevention, diagnosis, and ollow-up or prognosis o disease;andselection,optimization,andmonitoringo therapies. In this chapter, we begin with a general discussion to intro- duce the eld o laboratory medicine and the disciplines o clinical chemistry (or clinical biochemistry) and molecular diagnostics. T is will include a discussion o the meaning o the term laboratory medicine and the relationships among (1) clinical chemistry, (2) molecular diagnostics, (3) labora- tory medicine, and (4) evidence-based laboratory medicine. T e concepts introduced in this chapter are developed in the remaining chapters o this book. T e chapter concludes with a discussion on the ethical issues that clinical chemists/biochemists ace in the practice o their pro ession and issues that they will ace in the uture. Laboratory Medicine T e term laboratorymedicine re ers to the discipline involved in the (1) selection, (2) provision, and (3) interpretation o diagnostic testing that uses primarily samples rom patients. T is discipline includes (1) research, (2) administration, (3) teaching activities, and (4) clinical service. esting in labo- ratory medicine may be directed at (1) con rming a clinical suspicion,which mayinclude making,or rulingin,a diagnosis, (2) excluding, or ruling out, a diagnosis, (3) assisting in selec- tion, optimization, and monitoring o treatment, (4) providing a prognosis, (5) screening or disease in the absence o clinical
PART I Principles of Laboratory Medicine 2 signs or symptoms, and (6) establishing and monitoring the severity o a physiological disturbance (Box 1-1). T e eld o laboratory medicine includes clinical chem- istry and its traditional subdisciplines (including toxicology and drug monitoring, endocrine and organ unction test- ing, and “biochemical” and “molecular” genetics) and areas such as microbiology, hematology, hemostasis and throm- bosis, blood banking (trans usion medicine), immunology, and identity testing (Box 1-2). In some parts o the world, laboratory medicine also encompasses cytology and anatomic pathology (histopathology). In recent years, molecular diag- nostics has become an increasingly important part o all o the specialties o laboratory medicine. In ormation management and interpretation (including laboratory in ormatics) are key aspects o the laboratory medicine service, as are activities concerned with maintaining quality, such as (1) quality con- trol, (2) pro ciency testing, (3) audit, (4) benchmarking, and (5) clinical governance. Closer links with patients are increas- ingly attained through the use o telemedicine and tele-health- care, which includes acets o laboratory medicine such as (1) analytical testing, (2) the use o clinical decision support systems, and (3) in ormatics. Clinical Chemistry and Laboratory Medicine T e ties between clinical chemistry and other areas o labora- tory medicine have deep roots. Individuals working primar- ily in the area o clinical chemistry/biochemistry have devel- oped tools and methods that have become part o the abric o laboratory medicine beyond the clinical chemistry laboratory. Examples include (1) the theory and practice o re erence in- tervals (see Chapter 5), (2) the use o both (internal) quality control and pro ciency testing (see Chapter 7), (3) the intro- duction o automation into the clinical laboratory (see Chapter 16), and (4) concepts o diagnostic testing (see Chapters 3 and 4). From physician and patient perspectives, no distinction is evident among these specialties, and invariably the repertoire o more than one specialty will be called upon when a clini- cal decision is made. Examples o clinical scenarios that require tests rom multiple laboratory areas include the diagnosis and management o many diseases and the management o patients in intensive care (see Chapters 33 through 45). Boundaries between and among the parts o the clini- cal laboratory have become more blurred with increasing emphasis on the use o chemical and “molecular” (nucleic acid) testing. Molecular diagnostic testing has evolved beyond human genetic testing—an area in which clinical chemists have long been active. Now, clinical chemists in “molecular” laboratories contribute their expertise in laboratory medicine to in ectious disease testing, cancer diagnostics, and identity testing—activities that ormerly were associated primarily or solely with, respectively, clinical microbiology, hematology, and blood bank laboratories. Success ul contributions by clin- ical chemists to these areas require an understanding o the principles o laboratory medicine and close collaboration with clinical microbiologists, hematologists, and others who have specialized expertise in those areas o laboratory medicine. T e relationship between the clinical chemist and labora- tory medicine has evolved urther with the advent o “core” laboratories. T ese laboratories provide all o the high- volume and emergency testing in many hospitals. T eir e - cient and reliable operation depends on automation (see Chapter 16), computers, and high levels o quality control and quality management (see Chapter 7). Clinical chemists, who have long been active in these areas, have assumed increasing responsibility in core laboratories and thus have become more involved in areas such as hematology, coagulation, urinalysis, and even microbiology. T us a new type o “clinical chem- ist” has emerged, and again the unctions require a broader knowledge o laboratory medicine and greater collaboration with other specialists. A virtual merger o clinical chemistryand laboratorymedi- cine has been suggested in many ways. For example, journals in the eld o clinical chemistry publish articles in all o the areaso laboratorymedicine.T ecurrent logo o the American Association or Clinical Chemistry reads, “ AACC—Improving Healthcare through Laboratory Medicine.” Moreover, the BOX 1-1 Uses of Testing in the Clinical Laboratory • Con rminga clinicalsuspicion(whichcouldinclude makinga diagnosis) • Excluding a diagnosis • A ssisting in selection, optimization, and monitoring o treatment • Providing a prognosis • Screening or disease in the absence o clinical signs or symptoms • Establishing and monitoring the severityo a physiologicaldisturbance BOX 1-2 Disciplines of the Modern-Day Clinical Laboratory • BiochemicalGenetics • Cancer Diagnostics • ClinicalChemistry/Biochemistry • ClinicalHematology • ClinicalImmunology • Cytogenetics • Drug M onitoring • EndocrinologyT esting • Hemostasis/Thrombosis (Coagulation)T esting • IdentityT esting • In ectious Disease T esting • In ormationT echnology • LaboratoryM anagement • M icrobiology • M olecular Cytogenetics • M olecular Diagnostics • Nutrition • Organ T ransplantation • Organ Function T esting • Pharmacogenetics • Proteomics • QualityM anagement • T oxicology • T race Elements • T rans usion M edicine (Blood Banking)
CHAPTER 1 Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine 3 International Federation o Clinical Chemistry Societies is now called the International Federation o Clinical Chemistry and Laboratory Medicine (IFCC). Being active in the eld o laboratory medicine today requires, more o en than not, amiliarity with core concepts in several i not all o the sub- disciplines o the eld. During the past two decades, the eld o clinical chemistry has been pro oundly in uenced by new activities in the elds o clinical epidemiology and evidence-based medicine (see Chapter 4). Clinical epidemiologists have developed study designs to quanti y the diagnostic accuracy (as opposed to analytical accuracy) o tests developed in laboratory medicine (see Chapter 3). Moreover, they have introduced methods that are used to evaluate the ef ects and value o laboratory testing in healthcare (see Chapter 2). T ese developments are expected to play an increasing role in the selection and inter- pretation o tests. T us Chapter 4 o this book is devoted to evidence-based laboratory medicine. Molecular Diagnostics Molecular diagnostics is de ned as the use o the techniques o molecular biology or the purpose o prevention, diagnosis, ollow-up, or prognosis o disease. Molecular diagnostics has impacted all elds o laboratory medicine and has delivered several new diagnostic tools o proven clinical utility. A er the discovery o DNA as the repository o genetic in ormation in the 1950s, the development o molecular biology methods to studyDNAand RNA in the 1970s and 1980s, and the invention o the polymerase chain reaction (PCR) in 1985, analysis o nucleic acids and molecular biology methods have been used to decipher many biological processes o the living cell (see Chapters 46 to 49) in normal and disease states. T ese dis- coveries naturally led to the development o the discipline o molecular diagnostics, which entered the realm o laboratory medicine in multiple orms and in multiple elds. Molecular diagnostics has been applied to the study o the constitutive genome (e.g., inherited diseases, histocompatibility, identity assessment, pharmacogenetics; see Chapter 46) and to the study o acquired states (e.g., in ectious diseases, gra ing, and pregnancy). Molecular diagnostic methods can be qualitative or quantitative in nature, depending on the clinical need. T e eld o molecular diagnostics is characterized by very rapidly evolving technology (as the result o massive invest- ments in the human genome project and endeavors that ol- lowed), as well as by a rapidly increasing variety o potential clinical applications. O note, the advent o massively parallel nucleic acid sequencing is opening a wide spectrum o poten- tial new diagnostic applications, where tens to hundreds o millions o dif erent molecules are characterized and quanti- ed in a single experiment and supported by high throughput clinical bioin ormatic data analyses. Chapters 47, 48, and 49 provide an overview, respectively, o the Principles o Molecu- lar Biology, Nucleic Acid echniques and Applications, and Genome and Nucleic Acid Alterations. One eld in which molecular diagnostics has made a signi - icant impact is the studyo hematopoietic malignancies such as malignant lymphomas and leukemias. Easy access to malig- nant cells through a blood or bone marrow sample allowed the development o molecular biomarkers to re ne the diagnosis o such tumors. T ese include genetic rearrangements that are speci c to certain types o malignancies and are associ- ated with the aggressiveness and prognosis o the malignancy and, hence, are use ul tools or orienting treatment. Further, once the molecular signature o the patient’ s tumor has been identi ed, quantitative assays allow monitoring o response to therapy and aid in detection o residual disease in the event o a relapse and con rmation o durable remissions. Pharmacogenetics (see Chapter 46), or the study o varia- tion in drug metabolism between individuals, has been a eld o intensive work and increasing interest because studying the genomic DNA rom a patient is simpler than measuring the activity o enzymes in tissues that are not easily accessible but are involved in drug activation and metabolism. Apart rom the studyo tissues and nucleated cells, molecu- lar diagnostics has been applied to the study o plasma nucleic acids (or circulating nucleic acids; see Chapter 47). Plasma nucleic acid analysis has been made possible by the discovery that cells in the body release DNA and RNA into the extra- cellular compartment and ultimately into the bloodstream, where they can be detected and analyzed. Because o their short hal -li e in the circulation (less than 24 hours), plasma nucleic acids provide a measure o processes that are ongo- ing at the time o blood sampling. Such processes include the presence o nucleic acids rom abnormal tissue (tumor nucleic acids) or the existence o nonhost nucleic acids (microor- ganisms, gra –donor, and the etus during pregnancy). It is expected that molecular diagnostic analysis o plasma nucleic acids will enter routine clinical practice or various indications with the appearance o a high-quality evidence base or their clinical utility. Ethical Issues in Laboratory Medicine As in other branches o medicine, practitioners in laboratory medicine are aced with ethical issues, o en on a dailybasis;ex- amples are listed in Box 1-3. T e de nition o ethics varies, but in this chapter, the ollowing de nition is relevant: “T e rules or standards governing the conduct o an individual or the members o a pro ession (e.g., laboratory medicine).” Speci c ethical issues that pertain to the practice o laboratory medi- cine include but are not limited to (1) con dentiality o genetic in ormation and patient medical in ormation, (2) allocation BOX 1-3 Ethical Issues in Clinical Chemistry and Molecular Diagnostics • Con dentialityo genetic in ormation • Con dentialityo patient medicalin ormation • A llocation o resources • Codes o conduct • Publishing issues • Confict o interest
PART I Principles of Laboratory Medicine 4 o healthcare resources, (3) codes o conduct, (4) publishing issues, and (5) con ict o interest. Con dentiality o Genetic In ormation Prominent in the news in the rst and second decades o this millennium has been the issue o con dentiality o genetic in ormation. Legislation was considered necessary to prevent denial o health insurance or employment to people ound by DNA testing to be at risk o disease. Less appreciated is the act that the issue o con dentiality o clinical laboratory data pre- dated DNA testing. In act, manynon-DNA tests, old and new, also carry in ormation about risks o illness and death. Clini- cal laboratorians have long been responsible or maintaining the con dentiality o all laboratory results—a situation made even more critical with the advent o increasingly power ul genetic testing. Con dentiality o Patient Medical In ormation Because new medical tests are constantly needed, laboratory physicians and scientists spend a great deal o time and ef ort developing new diagnostic tests or evaluating them or use in a speci c setting. T is process requires use o patient samples and may involve use o patient medical in ormation.3 Ethical judgments are required regarding the type o in ormed con- sent that is needed rom patients or use o their samples and clinical in ormation. Clinical laboratory physicians and scien- tists o en serve on institutional review boards that examine proposed research on human subjects. In these discussions, ethical concepts such as equipoise and con dentiality are central to decision making. Allocation o Healthcare Resources Because resources are nite,clinicallaboratorians must make ethically responsible decisions about allocation o resources in the clinical laboratory and beyond. When a trade-of exists between cost and quality (o testing reagents or analyz- ers, or example), ethical issues may need to be considered: What is best or patients generally? How can the most good be done with the available resources? Busines s Ethics For laboratorians in business, the newly appreciated area o business ethics comes into play. One example, recently epito- mized by scandals associated with names such as Madof and Enron, involves the area o accounting—a human endeavor that in the public mind had not been much associated with concerns about ethics. Codes o Conduct Most pro essional organizations publish a Code o Conduct that requires adherence by their members. For example, the American Association or ClinicalChemistry(AACC)haspub- lished Ethical Guidelines (http://www.aacc.org/about/ethics/ Pages/de ault.aspx#; accessed June 26, 2013) that require AACC members to endorse principles o ethical conduct in their pro essional activities, including (1) selection and per- ormance o clinical procedures, (2) research and development, (3) teaching, (4) management, (5) administration, and (6) oth- er orms o pro essional service. Publishing Iss ues Publication o documents having high scienti c integrity de- pends on authors, editors, and reviewers all working in con- cert in an environment governed by high ethical standards.2 Authors are responsible or honest and complete report- ing o original data produced in ethically conducted research studies. Practices such as raud, plagiarism, and alsi cation or abrication o data are unacceptable! T e International Com- mittee o Medical Journal Editors (ICMJE)7 and the Commit- tee on Publication Ethics (COPE)5 have published policies that address such behavior. Other practices to be avoided include redundant publication, and inappropriate credit or author- ship; in addition, ethical policies require that actors that might in uence the interpretation o a study must be revealed. Most journals now have con ict o interest policies or both authors and journal editors. For example, Clinical Chemistry requires that authors complete a ull disclosure orm upon manuscript submission. Annually, the Editor and Associate Editors are also required to complete such a orm (http://www. clinchem.org/;accessed June 26, 2013). Conf ict o Interes t Concern has been raised over the interrelationships between practitioners in the medical eld and commercial suppliers o drugs, devices, equipment, etc., to the medical pro ession.8 T ese concerns led the National Institutes o Health (NIH) in 1995 to require o cial institutional review o nancial disclo- sure by researchers and management o situations in which disclosure indicates potential con ict o interest and/or con ict o ef ort in research. In 2009, the Institute o Medicine (IOM) issued a report6 that questioned inappropriate relationships between pharmaceutical and device companies and physicians and other healthcare pro essionals.8 Similarly, the relationships between clinical laboratorians and manu acturers and provid- ers o diagnostic equipment and supplies have been scrutinized. As a consequence o these concerns and as a result o the enactment o various laws designed to prevent raud, abuse, and waste in Medicare, Medicaid, and other ederal programs, pro essional organizations that represent manu acturers o in vitro diagnostics (IVD) and other device and healthcare companies have published Codes o Ethics. For example, the Advanced Medical echnology Association (AdvaMed) has revised and published its Code o Ethics that became ef ective July 1, 2009.1 opics discussed in this revised Code include (1) gi s and entertainment, (2) consulting arrangements and royalties, (3) reimbursement or testing, and (4) education. Similarly, the European Diagnostic Manu acturers Association (EDMA) has published its Code o Ethics.4 In Part A o this document, topics discussed include (1) member-sponsored product training and education, (2) supporting third-party educational con erences, (3) sales and promotional meetings, (4) nancial arrangements or consultants (5) gi s, (6) provi- sion o reimbursements and other economic in ormation, and (7) donations or charitable and philanthropic purposes.
CHAPTER 1 Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine 5 Both documents address demands rom regulators while nur- turing the unique role that laboratorians and other healthcare pro essionals play in developing and re ning new technology.8 In closing, it is our opinion that practitioners o clinical chemistry, molecular diagnostics, and laboratory medicine have be ore them a uture ull o promises and challenges. New insight into disease and its treatment is exploding, and these insights are based in sciences that are at the heart o the clinical laboratory. T e clinical laboratory is the place o translation o these insights into ef ective healthcare. We honor the impor- tant role o ethical laboratory pro essionals in these ef orts and have endeavored to provide in this book chapters prepared by expert authors that help to de ne the evidence base and the knowledge base o the pro ession. Review Questions 1. T e clinical laboratory discipline that is used most o en to assess inherited disease through study o the constitutive genome is: a. trans usion services. b. clinical chemistry. c. molecular diagnostics. d. hematology. 2. T e study o the genetic variation between individuals in their ability to metabolize drugs is re erred to as: a. pharmacogenetics. b. molecular diagnostics. c. clinical chemistry. d. epidemiology. 3. When a practitioner in clinical chemistry has an inappro- priate personal relationship with a commercial supplier o medical supplies and chemistry analyzers, there may be a potential issue with: a. publication development. b. con dentiality. c. selection o treatment. d. con ict o interest. 4. “Molecular testing” involves the clinical analysis o : a. atoms and molecules. b. nucleic acids. c. cellular components o blood. d. the physical structure o compounds. 5. Which one o the ollowing is not considered an ethical issue acing a clinical laboratorian? a. Allocation o resources b. Con icts o interest c. Discussion o one’ s salary d. Maintenance o con dentiality Re erences 1. Advanced Medical echnology Association (AdvaMed). Code o Ethics on interactions with health care pro essionals. Ef ective July 1, 2009. http://www.advamed.org/ (accessed on June 26, 2013). 2. Annesley M, Boyd JC, Ri ai N. Publication ethics: Clinical Chemistry editorial standards. Clin Chem 2009;55:1–4. 3. Council o Europe. Additional protocol to the convention or the protection o human rights and dignity o the human being with regard to the applica- tion o biology and medicine on biomedical research. Law Hum Genome Rev 2004;21:201–214. 4. European Diagnostic Manu acturers Association (EDMA). Part A: inter- action with health care pro essionals. http://www.edma-ivd.be/ (accessed June 26, 2013). 5. Gra C, Wager E, Bowman A, Fiack S, Scott-Lichter D, Robinson A. Best practice guidelines on publication ethics: a publisher’ s perspective. Int JClin Pract Suppl 2007;61:1–26. 6. Institute o Medicine. Con ict o interest in medical research, education, and practice. http://www.iom.edu (accessed June 26, 2013). 7. International Committee o Medical Journal Editors. Uni orm require- ments or manuscripts submitted to biomedical journals: writing and editing or biomedical publication. http://www.icmje.org/ (accessed June 26, 2013). 8. Malone B. Ethics code changes or diagnostics manu acturers. Clin Lab News 2009;35(6).
6 C H A P TE R Selection and Analytical Evaluation of Methods—With Statistical Techniques* *T e authors grate ully acknowledge the original contributions by T eodore Peters, Robert O. Kringle, and David D. Koch on which portions o this chapter are based. 2 Kristian Linnet, M.D., D.M.Sc., and James C. Boyd, M.D. Ob je c tive s 1. De ne the ollowing: A nalytical measurement range Median Bias Population Clinical sensitivity Precision Clinical speci city Random error Coe cient o variation Random sample Correlation coe cient Regression analysis Di erence plot Sample Error model Standard deviation Frequencydistribution Systematic error Gaussian probabilitydistribution Student t distribution Limit o detection T rueness Linearity U ncertainty Mean 2. List and describe three criteria that must be considerations in laboratorymethod selection, including the speci c parameters involved in each criterion. 3. Compare population and sample mean, population parameter and sample statistic, and population standard deviation and sample standard deviation, including a description o each, symbols used to express these, how they are calculated, and the in ormation theyprovide. 4. State the connection o the ollowing concepts to analytical methods: A ccuracy Linearity A nalytical sensitivity Precision A nalytical speci city Repeatability Calibration Reproducibility Limit o detection 5. List two common approaches used to objectively analyze data in a methods comparison study. 6. Describe the components o a di erence plot, including the plot’s use inmethodcomparisonandhowthe plotis interpreted. 7. Discuss assessment o error in an objective analysis o data in method comparison, including how error occurrence relates to anassay’s per ormance characteristics,the di erence between random and systematic error, what causes error, and howerror is evaluated in a di erence plot. 8. For the ollowing types o analyses, list the components o the analysis, its application in method comparison, how it is computed, how outliers a ect it, and how the results are interpreted: Deming regression Ordinaryleast-squares regression Nonparametric regression Regression 9. Describe the calibration hierarchy, including the tracing o val- ues o routine clinical chemistry measurements to a primary re erence, how the values are obtained, and the methods involved; draw a calibration hierarchygiven a speci c analyte. 10. Discuss the concept o uncertaintyin relation to clinicallabora- tory results, including the components o the standard uncer- tainty ormula and two ways in which uncertaintyis assessed. 11. Given appropriate values, state the ormula and calculate the ollowing: Coe cient o variation Population mean Coe cient o variation percent Precision analyses Deming regression Standard deviation Linear regression Standard uncertainty Ke y Wo rd s a n d De fin itio n s Analyte The substance being analyzed in an analytical procedure. Analyticalsensitivity The abilityo ananalyticalmethodtoassess small variations in the concentration o analyte. Analytical specif city The ability o an assay procedure to deter- mine speci cally the concentration o the target analyte in the presence o potentially inter ering substances or actors in the sample matrix. Bias In an analytical method, the di erence between the average value and the true value that is expressed numerically and is inverselyrelated to the trueness.
CHAPTER 2 Selection and Analytical Evaluation of Methods—With Statistical Techniques 7 T e introduction o new or revised methods is a common task or laboratoriansworkingin theclinicallaboratory(Figure2-1). In practice, a new or revised method must be selected care ully and its per ormance evaluated thoroughly in the laboratory be ore it is adopted or routine use. T e establishment o a new method may also involve an evaluation o the eatures o the automated analyzer on which the method will be implemented. Method evaluation in the clinical laboratory is in uenced strongly by guidelines (e.g., see the Clinical and Laboratory Standard Institute [CLSI; www.clsi.org/; accessed July 6, 2013] and the International Organization or Standardization [ISO; www.iso.org/; accessed July 6, 2013]). In addition, meeting laboratory accreditation requirements has become an impor- tant aspect o the method selection and evaluation process. T is chapter presents an overview o considerations in the method selection process, ollowed by sections on basic sta- tistics, method evaluation, and method comparison. A list o abbreviations used in this chapter is provided in Box 2-1. Method Selection Optimal method selection involves consideration o (1) medical use ulness, (2) analytical per ormance, and (3) practical criteria. Medical Use ulness Criteria T e selection o appropriate methods or clinical laboratory assays is a vital part o rendering optimal patient care, and ad- vances in patient care are requently based on the use o new or improved laboratory tests. Ascertaining what is necessary clinically rom a laboratory test is the rst step in selecting a candidate method (see Fig- ure 2-1). Keyparameters, such as desired turnaround time and necessary clinical utility or an assay, o en are derived rom discussions between laboratorians and clinicians. When new diagnostic assays are introduced, reliable estimates o clini- cal sensitivity and speci city must be obtained by reviewing the literature or by conducting a clinical outcome study. With established analytes (the substances analyzed in an analytical procedure), a common scenario is the replacement o an older, labor-intensive method with a newer, automated assay that is more economical or daily use. Analytical Per ormance Criteria In evaluating the per ormance characteristics o a candidate method, (1) precision, (2) accuracy (trueness), (3) analytical range, (4) detection limit, and (5) analytical speci city are o prime importance. T e sections in this chapter on method Ke y Wo rd s a n d De fin itio n s —c o n t’d Calibration In relation to analytical methods, a unction that describes the relationship between instrument signal and con- centration o analyte. Commutability The equivalence o the mathematicalrelationships between the results o di erent measurement procedures or a re erence materialand or representative samples romhealthy and diseased individuals. Di erence plot Abias plot that shows the dispersion o observed di erences between the measurements o two methods as a unction o the average concentration o the measurements; also re erred to as a “Bland-A ltman plot.” Limit o detection A nassaycharacteristicde nedas thelowestvalue that signi cantlyexceeds the measurements o a blanksample. Matrix In relation to analytical methods, human serum that con- tains analytes. Measuring interval The analyte concentration range over which measurements are within the declared tolerances or impreci- sion and bias; also re erred to as “reportable range.” Method comparison Comparison o measurements bytwo meth- ods that is carried out objectively using statistical procedures and graphics displays. Ordinary least-squares regression (OLR) analysis A method used to estimate the unknown parameters in a linear regres- sion assessment per ormed to minimize the sum o squared vertical distances between observed responses and responses predicted bylinear approximation. Population In relation to analytical methods, the complete set o all observations that might occur as the result o per orming a particular procedure according to speci ed conditions. Random error Error that arises rom imprecision o measure- ment o the type that is described by a Gaussian distribution (e.g., caused bypipetting variability, signal variability). Re erence measurement procedure Aprocedure o highest ana- lytical quality that has been shown to yield values having an uncertainty o measurement commensurate with its intended use,especiallyin assessing the trueness o other measurement procedures or the same quantity and in characterizing re er- ence materials. Regression analysis Astatistical analysis that compares meas- urement relations between two analytical methods. Systematic error Error in measurement that arises rom calibra- tion bias or nonspeci city o an assay and, in the course o a number o analyses o the same analyte, remains constant (y-intercept deviation rom zero)or varies in a proportionalway (slope deviation romunity)based on the analyte concentration. T raceability In relation to analytical methods, a concept based on a chain o comparisons o measurements that lead to a known re erence value done toensure reasonable agreement between measurements o routine methods. T rueness Aqualitative termthat describes the closeness o agree- ment between the average value obtained rom a large series o results o measurements and a true value. Uncertainty Aparameterassociatedwiththeresulto ameasurement that characterizes the dispersion o the values that could reason- ablybe attributed tothe measure and, or, more briefy, uncertainty is a parameter characterizing the range o values within which the value o the quantitybeing measured is expected tolie.
PART I Principles of Laboratory Medicine 8 evaluation and comparison contain outlines o these concepts and o their assessment. T e estimated per ormance param- eters or a method are related to quality goals that ensure ac- ceptable medical use o the test results (see section, “Analytical Goals”). From a practical point o view, the “ruggedness” o the method in routine use is o importance. When a new clinical analyzer is included in the overall evaluation process, various instrumental parameters also require evaluation, including (1) pipetting precision, (2) specimen-to-specimen carryover, (3) reagent-to-reagent car- ryover, (4) detector imprecision, (5) time to rst reportable result, (6) on-board reagent stability, (7) overall throughput, (8) mean time between instrument ailures,and (9) mean time to repair. In ormation on most o these parameters should be available rom the instrument manu acturer. Other (Practical) Criteria Various categories o candidate methods may be considered. New methods described in the scienti c literature may require “in-house” development. Commercial kit methods, on the other hand, are ready or implementation in the laboratory, o - ten in a “closed” analytical system on a dedicated instrument. When prospective methods are reviewed, attention should be given to the ollowing: 1. T e principle o the assay, with original re erences 2. T e detailed protocol or per orming the test 3. T e composition o reagents and re erence materials, the quantities provided, and their storage requirements (e.g., space, temperature, light, and humidity restrictions) applicable both be ore and a er the original containers are opened 4. T e stabilityo reagents and re erence materials (e.g., their shel li e) 5. echnologist time and required skills 6. Possible hazards and appropriate sa ety precautions according to relevant guidelines and legislation 7. T e type, quantity, and disposal o waste generated 8. Specimen requirements such as conditions or collec- tion, specimen volume requirements, the necessity or anticoagulants and preservatives, and necessary storage condition 9. T e re erence interval o the method, including in orma- tion on howit wasderived,typicalvaluesobtained in health and disease, and the necessity o determining a re erence interval or one’ s own institution (see Chapter 5 or details on how to generate a re erence interval) 10. Instrumental requirements and limitations 11. Cost-e ectiveness 12. Computer plat orms and inter acing to the laboratory in ormation system 13. T e availability o technical support, supplies, and service Other considerations should be taken into account. For example, is there suf cient space, electrical power, cooling, and plumbing or a newinstrument?Does the projected work- load match with the capacity o a new instrument? Is the test repertoire o a new instrument suf cient? What is the method o calibration, and what is its requency?Is staf ng o the labo- ratory suf cient or is training required? What are the appro- priate choices o quality control procedures and pro ciency testing? What is the estimated cost o per orming an assay using the proposed method, including the costs o calibrators, quality control specimens, and technologists’time? Basic Statistics In this section, undamental statistical concepts and techniques are introduced in the context o typical analytical investiga- tions. T e basic concepts o populations, samples, parameters, Quality control practices Routine analysis Implementation Method verification/ validation Method selection/ development Definition of quality goal Establish need Result report Figure 2-1 Flow diagram that illustrates the process o intro- ducing a new method into routine use. The diagram highlights the key steps o method selection, method evaluation, and qual- ity control. BOX 2-1 Abbreviations CI Con dence interval CV Coe cient o variation (=SD/x, where xis the concentration) CV % = CV100% CV A A nalyticalcoe cient o variation CV RB Randombias coe cient o variation ISO InternationalOrganization or Standardization OLR Ordinaryleast-squares regression analysis SD Standard deviation SEM Standard error o the mean = SD⁄√ N) SDA A nalyticalstandard deviation SDRB Randombias standard deviation xm M ean
CHAPTER 2 Selection and Analytical Evaluation of Methods—With Statistical Techniques 9 statistics, and probability distributions are de ned and illus- trated. wo important probability distributions, Gaussian and Student t, are introduced and discussed. Frequency Dis tribution A graphical device or displaying a large set o data is the re- quency distribution, also called a histogram. Figure 2-2 shows a requency distribution displaying the results o serum γ-glutamyltrans erase (GG ) measurements o 100 apparently healthy 20- to 29-year-old men. T e requency distribution is constructed by dividing the measurement scale into cells o equal width, counting the number, ni, o values that all within each cell, and drawing a rectangle above each cell whose area (and height, because all cell widths are equal) is proportional to ni. In this example, the selected cells were 5 to 9, 10 to 14, 15 to 19, 20 to 24, 25 to 29, and so on, with 60 to 64 being the last cell. T e ordinate axis o the requency distribution gives the number o values alling within each cell. When this number is divided by the total number o values in the data set, the rela- tive requency in each cell is obtained. O en, the position o a subject’ s value within a distribu- tion o values is use ul medically. T e nonparametricapproach is used to determine directly the percentile o a given subject. When N subjects have been ranked according to their values, the n-percentile, Percn, may be estimated as the value o the (N[n/100] + 0.5) ordered observation. In cases o a noninteger value, interpolation is carried out between neighboring values. Population and Sample T e purpose o analytical work is to obtain in ormation and draw conclusions about characteristics o one or more popu- lations o values. In the GG example, the interest involves the location and spread o the population o GG values or 20- to 29-year-old healthy men. T us a working de nition o a population is the complete set o all observations that might occur as a result o per orming a particular procedure accord- ing to speci ed conditions. Most populations o interest in clinical chemistry are in - nite in size and so are impossible to study in their entirety. Usually a subgroup o observations is taken rom the popula- tion as a basis on which conclusions can be ormed about the population characteristics. T e group o observations that has actually been selected rom the population is called a sample. For example, the 100 GG values represent a sample rom a respective population. However, a sample is used to study the characteristics o a population only i it has been properly selected. For instance, i the analyst is interested in the popu- lation o GG values over various lots o materials and some time period, the sample must be selected to be representative o these actors as well as o the age, sex, and health actors. Consequently, exact speci cation o the population(s) o inter- est is necessary be ore a plan can be designed or obtaining the sample(s). Probability and Probability Distributions Consider again the requency distribution in Figure 2-2. In addition to the general location and spread o the GG determinations, other use ul in ormation is easily extracted rom this requency distribution. For instance, 96% (96 o 100) o the determinations are less than 55 U/L, and 91%(91 o 100) are greater than or equal to 10 but less than 50 U/L. Because the cell interval is 5 U/Lin this example, statements like these can be made only to the nearest 5 U/L. A larger sample would allow a smaller cell interval and more re ned statements. For a suf ciently large sample, the cell interval is made so small that the requency distribution is approx- imated by a continuous, smooth curve like that shown in Figure 2-3. In act, i the sample is large enough, we can consider this a close representation o the true population requency distribution. In general, the unctional orm o the population requency distribution curve o a variable x is denoted by (x). T e population requency distribution allows us to make probability statements about the GG o a randomly selected member o the population o healthy 20- to 29-year-old men. For example, the probability Pr(x > xa) that the GG value x o a randomly selected 20- to 29-year-old healthy man is greater than some particular value xa is equal to the area under the population requency distribution to the right o xa. I xa = 58, then rom Figure 2-3, Pr(x > 58) = 0.05. Similarly, the prob- ability Pr(xa < x < xb) that x is greater than xa but less than xb is equal to the area under the population requency distribution between xa and xb. For example, i xa = 9 and xb = 58, then rom Figure 2-3, Pr(9 < x < 58) = 0.90. Because the popula- tion requency distribution provides all in ormation about the probabilities o a randomly selected member o the popula- tion, it is called the probability distribution o the population. Although the true probability distribution is never exactly 5 0.05 10 0.90 0.05 15 20 25 30 35 40 GGT (U/L) 45 50 55 60 65 x 0.1 0.2 0.3 R e l a t i v e f r e q u e n c y f ( x) Figure 2-3 Population requency distribution o γ-GGT values. 5 10 15 20 GGT (U/L) 25 30 35 40 45 50 55 60 65 10 3 10 17 29 14 8 5 5 3 2 3 1 0 0.10 R e l a t i v e f r e q u e n c y n i / Σ n i F r e q u e n c y n i 0.20 0.30 20 30 Figure 2-2 Frequency distribution o 100 γ-GGT values.
PART I Principles of Laboratory Medicine 10 known in practice, it is approximated with a large sample o observations. Parameters : Descriptive Meas ures o a Population Any population o values can be described by measures o its characteristics. A parameter is a constant that describes some particular characteristic o a population. Although most pop- ulations o interest in analytical work are in nite in size, or the ollowing de nitions we shall consider the population to be o nite size N, where N is very large. One important characteristic o a population is its central location. T e parameter most commonly used to describe the central location o a population o N values is the population mean (µ): µ= xi N An alternative parameter that indicates the central ten- dency o a population is the median, which is de ned as the 50th percentile, Perc50. Another important characteristic o a population is the dispersion o values about the population mean. A parameter very use ul in describing this dispersion o a population o N values is the population variance σ2 (sigma squared): (xi − µ)2 N 2 = T e population standard deviation σ, the positive square root o the population variance, is a parameter requently used to describe the population dispersion in the same units (e.g., mg/dL) as the population values. Statistics: Des criptive Measures o the Sample As was noted earlier, the clinical laboratorian usually has available only a ew observations rom the population o in- terest. A statisticis a value calculated rom the observations in a sample to describe a particular characteristic o that sample. T e sample mean xm is the arithmetic average o a sample, which is an estimate o µ. Likewise, the sample standard devi- ation (SD) is an estimate o σ, and the coef cient o variation (CV) is the ratio o the SD to the mean multiplied by 100%. T e equations used to calculate xm, SD, and CV, respectively, are as ollows: xm = xi N SD= (xi − xm)2 N− 1 = xi 2 − ( xi)2 N N− 1 CV= SD xm × 100% where xi is an individual measurement, and N is the number o sample measurements. Random Sampling A random selection rom a population is one in which each member o the population has an equal chance o being se- lected. A random sample is one in which each member o the sample is considered to be a random selection rom the popu- lation o interest. Although much o statistical analysis and in- terpretation depends on the assumption o a random sample rom some xed population, actual data collection o en does not satis y this assumption. In particular, or sequentially gen- erated data, it is o en true that observations adjacent to each other tend to be more alike than observations separated in time. A sample o such observations cannot be considered a sample o random selections rom a xed population. Fortu- nately, precautions can usually be taken in the design o an investigation to validate approximately the random sampling assumption. The Gauss ian Probability Distribution T e Gaussian probability distribution, which is illustrated in Figure 2-4, is o undamental importance in statistics or sev- eral reasons. As was mentioned earlier, a particular analytical value x will not usually be equal to the true value µ o the speci- men being measured. Rather, associated with this particular value x will be a particular measurement error, ε = x − µ, which is the result o many contributing sources o error. T ese mea- surement errors tend to ollow a probability distribution like that shown in Figure 2-4, where the errors are symmetrically distributed, with smaller errors occurringmore requentlythan larger ones, and with an expected value o 0. T is important act is known as the central limit e ect or distribution o er- rors: I a measurement error ε is the sum o many independent sources o error (ε1, ε2, …, εk), several o which are major con- tributors, the probabilitydistribution o the measurement error ε will tend to be Gaussian as the number o sources o error becomes large. Another reason or the importance o the Gaussian prob- ability distribution is that many statistical procedures are based on the assumption o a Gaussian distribution o values; this approach is commonly re erred to as parametric. Further- more, these procedures usually are not seriously invalidated by departures rom this assumption. Finally, the magnitude − − − Figure 2-4 The Gaussian probability distribution.
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf
Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf

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Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics ( PDFDrive ).pdf

  • 1.
  • 3. PART I PRINCIPLES OF LABORATORY MEDICINE, 1 1 . Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine, 1 2 . Selection and Analytical Evaluation of Methods—With Statistical Techniques, 6 3 . Clinical Evaluation of Methods, 33 4 . Evidence-Based Laboratory Medicine, 40 5 . Establishment and Use of Reference Values, 60 6 . Specimen Collection, Processing, and Other Preanalytical Variables, 72 7 . Quality Management, 90 8 . Principles of Basic Techniques and Laboratory Safety, 107 PART II ANALYTICAL TECHNIQUES AND INSTRUMENTATION, 129 9 . Optical Techniques, 129 1 0 . Electrochemistry and Chemical Sensors, 151 1 1 . Electrophoresis, 171 1 2 . Chromatography, 183 1 3 . Mass Spectrometry, 202 1 4 . Enzyme and Rate Analyses, 216 1 5 . Immunochemical Techniques, 236 1 6 . Automation, 254 1 7 . Point-of-Care Instrumentation, 272 PART III ANALYTES, 286 1 8 . Amino Acids, Peptides, and Proteins, 286 1 9 . Serum Enzymes, 318 2 0 . Tumor Markers and Cancer Genes, 337 2 1 . Kidney Function Tests—Creatinine, Urea, and Uric Acid, 364 2 2 . Carbohydrates, 376 2 3 . Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors, 388 2 4 . Electrolytes and Blood Gases, 412 2 5 . Hormones, 430 2 6 . Catecholamines and Serotonin, 442 2 7 . Vitamins, Trace Elements, and Nutritional Assessment, 459 2 8 . Hemoglobin, Iron, and Bilirubin, 499 2 9 . Porphyrins and Porphyrias, 522 3 0 . Therapeutic Drugs and Their Management, 536 3 1 . Clinical Toxicology, 559 3 2 . Toxic Metals, 592 Contents
  • 4. PART IV PATHOPHYSIOLOGY, 608 3 3 . Diabetes, 608 3 4 . Cardiovascular Disease, 632 3 5 . Kidney Disease, 651 3 6 . Physiology and Disorders of Water, Electrolyte, and Acid-Base Metabolism, 680 3 7 . Liver Disease, 700 3 8 . Gastrointestinal and Pancreatic Diseases, 724 3 9 . Disorders of Bone and Mineral Metabolism, 741 4 0 . Disorders of the Pituitary, 769 4 1 . Disorders of the Adrenal Cortex, 785 4 2 . Thyroid Disorders, 806 4 3 . Reproduction-Related Disorders, 824 4 4 . Pregnancy and Prenatal Testing, 848 4 5 . Newborn Screening and Inborn Errors of Metabolism, 870 4 6 . Pharmacogenetics, 885 PART V MOLECULAR DIAGNOSTICS, 899 4 7 . Principles of Molecular Biology, 899 4 8 . Nucleic Acid Techniques and Applications, 915 4 9 . Genomes and Nucleic Acid Variations, 946 PART VI REFERENCE INFORMATION, 951 5 0 . Reference Information for the Clinical Laboratory, 951
  • 6. Y ou can now purchase Elsevier products on Evolve! Go to evolve.elsevier.com/html/shop-promo.html to search and browse for products. Activate the complete learning experience that comes with each NEW textbook purchase by registering at Evolve Student Resources for Burtis: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, Seventh Edition, include the following features: Chapter Review Question Answer Key Case Studies http://evolve.elsevier.com/Tietz/fundamentals/ Y O U ’V EJU STPU RCH A SED M O RET H A N AT EX T BO O K ! REGISTER TODA Y!
  • 7. Tietz Fundamentals of CLINICAL CHEMISTRY AND MOLECULAR DIAGNOSTICS Carl A. Burtis, Ph.D. Emeritus Oak Ridge National Laboratory Oak Ridge, Tennessee Clinical Professor of Pathology University of Utah School of Medicine Salt Lake City, Utah David E. Bruns, M.D. Professor of Pathology University of Virginia School of Medicine Director of Clinical Chemistry and Associate Director of Molecular Diagnostics University of Virginia Health System Charlottesville, Virginia Consulting Editor Barbara G. Sawyer, Ph.D., M.L.S. (A.S.C.P.)CM , MB (A.S.C.P.)CM Professor, Clinical Laboratory Science/ Molecular Pathology Texas Tech University Health Sciences Center Lubbock, Texas Seventh Edition
  • 8. 3251 Riverport Lane St. Louis, Missouri 63043 IE Z FUNDAMEN ALSOF CLINICAL CHEMIS RY , SEVEN H EDI ION ISBN: 978-1-4557-4165-6 Copyright © 2015 by Saunders, an imprint of Elsevier Inc. No part o this publication may be reproduced or transmitted in any orm or by any means, electronic or mechani- cal, including photocopying, recording, or any in ormation storage and retrieval system, without permission in writing rom the publisher. Details on how to seek permission, urther in ormation about the Publisher’ s permis- sions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be ound at our website: www.elsevier.com/permissions. T is book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this f eld are constantly changing. As new research and experience broaden our understanding, changes in research methods, pro essional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any in ormation, methods, compounds, or experiments described herein. In using such in ormation or methods they should be mind ul o their own sa ety and the sa ety o others, including parties or whom they have a pro essional responsibility. With respect to any drug or pharmaceutical products identif ed, readers are advised to check the most current in ormation provided (i) on procedures eatured or (ii) by the manu acturer o each product to be administered, to veri y the recommended dose or ormula, the method and duration o administration, and contraindications. It is the responsibility o practitioners, relying on their own experience and knowledge o their patients, to make diagnoses, to determine dosages and the best treatment or each individual patient, and to take all appropriate sa ety precautions. o the ullest extent o the law, neither the Publisher nor the authors, contributors, or editors, assume any liability or any injury and/or damage to persons or property as a matter o products liability, negligence or otherwise, or rom any use or operation o any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2008, 2001, 1996, 1987, 1976, 1971 ISBN:978-1-4557-4165-6 Content Development Manager: Ellen Wurm-Cutter Content Development Specialist: Andrea Hunolt PublishingServices Manager: Julie Eddy Senior Project Managers: Andrea Campbell, Celeste Clingan Design Direction: Paula Catalano Printed in the United States o America Last digit is the print number: 9 8 7 6 5 4 3 2 1
  • 9. Dedication to Seventh Edition Mentor, Colleague, Friend On behal o the worldwide community o clinical laboratorians, we are pleased to dedicate this edition o the Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics to Pro essor Norbert W. ietz, Ph.D. T rough his many scienti c, educational, and editorial ef orts, Pro essor ietz has had a signi cant and worldwide impact on the pro ession, practice, and teachingo clinical laboratory medicine. Pro essor ietz is internationally known or creatingand subsequent editingo one o the rst books produced or clinical laboratorians, the internationally acclaimed Fundamentals of Clinical Chemistry. It was the rst modern textbook that integrated clinical chemistry with the basic medical sciences and pathophysiology. Dr. ietz also edited the rst edition o the Textbook of Clinical Chemistry, a re erence text that bridges the gap between the clinical laboratory and medical management by relatingpathophysiology to analytical results in health and disease. He has also edited the Clinical Guide to Laboratory Tests and the Applied Laboratory Medicine. In summary, Pro essor ietz has been and continues to be a strong advocate o clinical chemistry, and through his energetic scienti ic, educational, and editorial e orts he has encouraged countless clinical chemists, clinical pathologists, and medical technologists to advance their pro ession by linking progress in laboratory medicine with the practice o medicine. he name o ietz is synonymous with the pro ession and practice o quality laboratory medicine. It is our distinct pleasure to dedicate this edition o the Fundamentals of Clinical Chemistry and Molecular Diagnostics to an individual who has had such a signi icant impact on our pro ession and our careers.
  • 11. vii T omas M. Annesley, Ph.D. Emeritus Pro essor University o Michigan Medical School Ann Arbor, Michigan; Deputy Editor, Clinical Chemistry Washington, D.C. Mass Spectrometry Fred S. Apple, Ph.D. Medical Director o Clinical Laboratories Hennepin County Medical Center, Pro essor o Laboratory Medicine and Pathology University o Minnesota School o Medicine Minneapolis, Minnesota Cardiovascular Disease Edward R. Ashwood, M.D. Pro essor o Pathology University o Utah School o Medicine; President and Chie Executive O cer ARUP Laboratories Salt Lake City, Utah Clinical Evaluation of Methods Michael N. Badminton, M.B., Ch.B., Ph.D., F.R.C.Path. Honorary Consultant and Clinical Lead, National Acute Porphyria Service (Cardi ) Medical Biochemistry & Immunology University Hospital o Wales; Senior Lecturer Institute o Molecular and Experimental Medicine School o Medicine, Cardi University Heath Park, Cardi Porphyrins and Porphyrias Renze Bais, Ph.D., F.F.Sc. (R.C.P.A.) rbaisconsulting.com Sydney, NSW Australia Enzyme and Rate Analyses; Serum Enzymes James C. Barton, M.D. Director, Southern Iron Disorders Center; Clinical Pro essor o Medicine Department o Medicine University o Alabama at Birmingham Birmingham, Alabama Hemoglobin, Iron, and Bilirubin Lindsay A.L. Bazydlo, Ph.D. Co-Director Clinical Chemistry, University o Florida Health Shands Hospital Director Clinical oxicology, University o Florida Health PathLabs Assistant Pro essor Department o Pathology, Immunology, and Laboratory Medicine University o Florida College o Medicine Gainesville, Florida Electrophoresis Laura K. Bechtel, Ph.D., D.A.B.C.C. Laboratory Director Forensic Laboratories, Inc. Denver, Colorado Clinical oxicology Roger L. Berthol , Ph.D. Pro essor o Pathology Director o Clinical Chemistry, oxicology, and Point o Care esting University o Florida Health Science Center Jacksonville, Florida Disorders of the Pituitary; Disorders of the Adrenal Cortex; T yroid Disorders Patrick M.M. Bossuyt, Ph.D. Pro essor o Clinical Epidemiology Academic Medical Center University o Amsterdam Amsterdam, T e Netherlands Evidence-Based Laboratory Medicine James C. Boyd, M.D. Associate Pro essor o Pathology Chie , Division o Clinical Pathology University o Virginia Medical School Director o Systems Engineering and Core Lab Automation Associate Director o Clinical Chemistry and oxicology University o Virginia Health System Charlottesville, Virginia; Deputy Editor, Clinical Chemistry Washington, D.C. Selection and Analytical Evaluation of Methods—With Statistical echniques; Automation Contributors
  • 12. Contributors viii David E. Bruns, M.D. Pro essor o Pathology University o Virginia School o Medicine Director o Clinical Chemistry and Associate Director o Molecular Diagnostics University o Virginia Health System Charlottesville, Virginia Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine; Clinical Evaluation of Methods; Evidence-Based Laboratory Medi- cine; Reference Information Carl A. Burtis, Ph.D. Emeritus Oak Ridge National Laboratory Oak Ridge ennessee Clinical Pro essor o Pathology University o Utah School o Medicine Salt Lake City, Utah Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine; Chromatography; Reference Information Daniel W. Chan, Ph.D., D.A.B.C.C., F.A.C.B. Pro essor o Pathology, Oncology, Radiology, and Urology Director o Clinical Chemistry Division Department o Pathology, Director, Center or Biomarker Discovery Johns Hopkins Medical Institutions Baltimore, Maryland umor Markers and Cancer Genes Rossa W.K. Chiu, M.B.B.S, Ph.D., F.R.C.P.A., F.H.K.A.M. (Pathology) Pro essor Department o Chemical Pathology T e Chinese University o Hong Kong Honorary Consultant Department o Chemical Pathology Prince o Wales Hospital Hong Kong, SAR, China Principles of Molecular Biology Allan C. Deacon, Ph.D., F.R.C.Path. Consultant Clinical Scientist Clinical Biochemistry Department Bed ord Hospital Bed ordshire, United Kingdom Porphyrins and Porphyrias Michael P. Delaney, B.Sc., M.D., F.R.C.P. Consultant Nephrologist East Kent Hospitals NHSFoundation rust Canterbury, Kent, United Kingdom Kidney Disease Mari L. DeMarco, Ph.D. Clinical Assistant Pro essor University o British Columbia, Clinical Chemist St. Paul’ s Hospital Department o Pathology and Laboratory Medicine Vancouver, British Columbia, Canada Reproduction-Related Disorders Paul D’Orazio, Ph.D. Director Critical Care Analytical Instrumentation Laboratory Co. Bed ord, Massachusetts Electrochemistry and Chemical Sensors Basil . Doumas, Ph.D. Pro essor Emeritus Department o Pathology Medical College o Wisconsin Milwaukee, Wisconsin Hemoglobin, Iron, and Bilirubin D. Robert Du our, M.D. Consultant, Pathology and Hepatology Veterans A airs Medical Center, Emeritus Pro essor o Pathology George Washington University Medical Center Washington, D.C. Liver Disease John H. Eck eldt, M.D. Vice Chair or Clinical A airs Department o Laboratory Medicine and Pathology University o Minnesota Medical School Minneapolis, Minnesota Hemoglobin, Iron, and Bilirubin Graeme Eisenho er, Ph.D. Pro essor Department o Medicine III Institute o Clinical Chemistry and Laboratory Medicine Chie , Division o Clinical Neurochemistry University Hospital Carl Gustav Carus Dresden at the Dresden University o echnology Dresden, Germany Catecholamines and Serotonin George H. Elder, M.D., F.R.C.P., F.R.C.Path. Emeritus Pro essor Department o Medical Biochemistry and Immunology School o Medicine, Cardi University Cardi , United Kingdom Porphyrins and Porphyrias Jens Peter Goetze, M.D., D.M.Sc. Pro essor, Chie Physician Department o Clinical Biochemistry Rigshospitalet University o Copenhagen and Aarhus Copenhagen, Denmark Cardiovascular Disease David G. Grenache, Ph.D., M. . (A.S.C.P.), D.A.B.C.C., F.A.C.B. Associate Pro essor o Pathology University o Utah School o Medicine Medical Director, Special Chemistry ARUP Laboratories Salt Lake City, Utah Pregnancy and Prenatal esting
  • 13. Contributors ix Ann M. Gronowski, Ph.D. Pro essor, Department o Pathology and Immunology Pro essor, Department o Obstetrics and Gynecology Washington University School o Medicine St. Louis, Missouri Reproduction-Related Disorders Amy R. Groszbach, M.E.D., M.L. ., M.B. (A.S.C.P.)CM Education Program Coordinator Molecular Genetics Laboratory, Mayo Clinic Program Director, Molecular Genetics echnology Internship Program Mayo School o Health Science Mayo Clinic Rochester, Minnesota Specimen Collection, Processing, and Other Preanalytical Variables Doris M. Haverstick, Ph.D., D.A.B.C.C. Associate Pro essor o Pathology University o Virginia Charlottesville, Virginia Specimen Collection, Processing, and Other Preanalytical Variables Charles D. Hawker, Ph.D., M.B.A., F.A.C.B. Adjunct Pro essor o Pathology University o Utah School o Medicine ARUP Laboratories Salt Lake City, Utah Automation re or Higgins, M.Sc., F.C.A.C.B. Director o Clinical Chemistry GynaLIFEDX Clinical Pro essor Department o Laboratory Medicine and Pathology Faculty o Medicine University o Alberta Edmonton, Alberta Hemoglobin, Iron, and Bilirubin Peter G. Hill, Ph.D., F.R.C.Path. Emeritus Consultant Clinical Biochemistry Royal Derby Hospital Derby, United Kingdom Gastrointestinal and Pancreatic Diseases Christopher P. Holstege, M.D. Chie , Division o Medical oxicology Associate Pro essor, Department o Emergency Medicine and Pediatrics University o Virginia School o Medicine Medical Director, Blue Ridge Poison Center University o Virginia Health System Charlottesville, Virginia Clinical oxicology Gary L. Horowitz, M.D. Associate Pro essor o Pathology Harvard Medical School Director o Clinical Chemistry Beth Israel Deaconess Medical Center Boston, Massachusetts Establishment and Use of Reference Values Glen L. Hortin, M.D., Ph.D. Clinical Pathology Medical Director, Southeast Region Quest Diagnostics ampa, Florida Chromatography; Amino Acids, Peptides, and Proteins Allan S. Jaf e, M.D. Consultant in Cardiology and Laboratory Medicine Pro essor o Medicine Pro essor o Laboratory Medicine and Pathology Chair, CCLSDivision o Laboratory Medicine and Pathology Mayo Clinic and Medical School Rochester, Minnesota Cardiovascular Disease Ishwarlal Jialal, M.D., Ph.D., F.R.C.Path. (London), D.A.B.C.C. Robert E. Stowell Endowed Chair in Experimental Pathology Director o the Laboratory or Atherosclerosis and Metabolic Research Distinguished Pro essor o Pathology and Internal Medicine (Endocrinology, Diabetes, and Metabolism) University o Cali ornia Davis Medical Center Sacramento, Cali ornia Disorders of the Pituitary; Disorders of the Adrenal Cortex George G. Klee, M.D., Ph.D. Emeritus Pro essor o Laboratory Medicine and Pathology College o Medicine Department o Laboratory Medicine and Pathology Mayo Clinic Rochester, Minnesota Quality Management Michael Kleerekoper, M.D., F.A.C.B., F.A.C.P., M.A.C.E. Clinical Pro essor o Internal Medicine/Endocrinology College o Medicine and Li e Sciences University o oledo oledo, Ohio Hormones; Disorders of Bone and Mineral Metabolism Larry J. Kricka, D.Phil, F.A.C.B., C.Chem., F.R.S.C., F.R.C.Path. Pro essor University o Pennsylvania Department o Pathology and Laboratory Medicine Director o General Chemistry and the Critical Care Laboratory Hospital o the University o Pennsylvania Philadelphia, Pennsylvania Optical echniques; Immunochemical echniques Noriko Kusukawa, Ph.D. Director, New echnology Assessment and Licensing ARUP Laboratories Adjunct Associate Pro essor o Pathology University o Utah School o Medicine Salt Lake City, Utah Nucleic Acid echniques and Applications; Genomes and Nucleic Acid Variations Edmund J. Lamb, Ph.D., F.R.C.Path. Head, Department o Clinical Biochemistry East Kent Hospitals NHSFoundation rust Canterbury, Kent, United Kingdom KidneyFunction ests—Creatinine, Urea, and UricAcid;KidneyDisease
  • 14. Contributors x Geralyn Lambert-Messerlian, Ph.D., F.A.C.B. Pro essor Department o Pathology and Laboratory Medicine Alpert Medical School o Brown University Director Division o Medical Screening and Special esting Women and In ants Hospital Providence, Rhode Island Pregnancy and Prenatal esting James P. Landers, Ph.D. Pro essor o Chemistry Pro essor o Mechanical Engineering University o Virginia Associate Pro essor o Pathology University o Virginia Health System Charlottesville, Virginia Electrophoresis Loralie Langman, Ph.D., F.C.A.C.B., D.A.B.C.C. (C.C., M.B., .C.), D.A.B.F. . Director, oxicology and Drug Monitoring Laboratory Department o Laboratory Medicine and Pathology Mayo Clinic Associate Pro essor o Laboratory Medicine and Pathology Mayo Clinic College o Medicine Rochester, Minnesota Clinical oxicology Vicky A. LeGrys, Ph.D., Dr.A., M. . (A.S.C.P.) C.L.S. (N.C.A.) Pro essor Division o Clinical Laboratory Science School o Medicine University o North Carolina at Chapel Hill Chapel Hill, North Carolina Electrolytes and Blood Gases Kristian Linnet, M.D., Ph.D. Pro essor, Chie , Section o Forensic Chemistry Department o Forensic Medicine Faculty o Health Sciences University o Copenhagen Copenhagen, Denmark Selection and Analytical Evaluation of Methods—With Statistical echniques Stanley F. Lo, Ph.D., D.A.B.C.C., F.A.C.B. Associate Pro essor o Pathology Medical College o Wisconsin Associate Director, Clinical Laboratories Children’ s Hospital o Wisconsin Milwaukee, Wisconsin Principles of Basic echniques and Laboratory Safety Y.M. Dennis Lo, M.A., D.M., D.Phil., F.R.C.P., F.R.C.Path., F.R.S. Li Ks Shing Pro essor o Medicine Pro essor o Chemical Pathology Department o Chemical Pathology T e Chinese University o Hong Kong Prince o Wales Hospital Hong Kong S.A.R., China Principles of Molecular Biology Nicola Longo, M.D., Ph.D., F.A.C.M.G. Pro essor o Pediatrics and Pathology Chie , Division o Medical Genetics Department o Pediatrics, Medical Co-Director, ARUP Biochemical Genetics Laboratory, University o Utah Salt Lake City, Utah Newborn Screening and Inborn Errors of Metabolism Gwendolyn A. McMillin, Ph.D., D.A.B.C.C. (C.C., .C.) Assistant Pro essor (Clinical) o Pathology University o Utah School o Medicine Medical Director, oxicology, race Elements, Pharmacogenomics ARUP Laboratories Salt Lake City, Utah T erapeutic Drugs and T eir Management; Pharmacogenetics; Refer- ence Information Mark E. Meyerhof , Ph.D. Philip J. Elving Pro essor o Chemistry Department o Chemistry T e University o Michigan Ann Arbor, Michigan Electrochemistry and Chemical Sensors T omas P. Moyer, Ph.D. Pro essor o Laboratory Medicine Department o Laboratory Medicine & Pathology Mayo College o Medicine Mayo Clinic Rochester, Minnesota oxic Metals Mauro Panteghini, M.D. Pro essor o Clinical Biochemistry and Clinical Molecular Biology Department o Biomedical and Clinical Sciences “Luigi Sacco” University o Milan Director, Clinical Pathology Laboratory Ospedale “Luigi Sacco” Milan, Italy Enzyme and Rate Analyses; Serum Enzymes Jason Y. Park, M.D., Ph.D., F.C.A.P. Assistant Pro essor Department o Pathology University o exas Southwestern Medical Center Director Advanced Diagnostics Laboratory Children’ s Medical Center Dallas, exas Optical echniques; Immunochemical echniques Marzia Pasquali, Ph.D., F.A.C.M.G. Pro essor o Pathology University o Utah School o Medicine Medical Director, Biochemical Genetics and Supplemental Newborn Screening ARUP Laboratories Salt Lake City, Utah Newborn Screening and Inborn Errors of Metabolism
  • 15. Contributors xi Christopher P. Price, Ph.D., F.R.S.C., F.R.C.Path. Visiting Pro essor in Clinical Biochemistry Department o Primary Care Health Sciences University o Ox ord Ox ord, United Kingdom Evidence-Based Laboratory Medicine; Point-of-Care Instrumentation; Kidney Function ests—Creatinine, Urea, and Uric Acid; Kidney Disease Alex J. Rai, Ph.D., D.A.B.C.C., F.A.C.B. Director, Special Chemistry Laboratory New Y ork Presbyterian Hospital Associate Pro essor o Pathology and Cell Biology Chie Scientif c O cer, Center or Advanced Laboratory Medicine Department o Pathology and Cell Biology Columbia University Medical Center New Y ork, New Y ork umor Markers and Cancer Genes Alan . Remaley, M.D., Ph.D. Department o Laboratory Medicine National Institutes o Health Bethesda, Maryland Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors Nader Ri ai, Ph.D. T e Louis Joseph Gay-Lussac Chair in Laboratory Medicine Director o Clinical Chemistry Boston Children’ s Hospital Pro essor o Pathology Harvard Medical School Boston, Massachusetts Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors Juha Risteli, M.D, Ph.D., F.E.B.M.B. Pro essor o Clinical Chemistry Department o Clinical Chemistry Institute o Diagnostics University o Oulu Oulu, Finland Disorders of Bone and Mineral Metabolism Leila Risteli, M.D., Ph.D., M.A., F.E.B.M.B. Chie Physician Northern Finland Laboratory Centre (NordLab) Adjunct Pro essor o Medical Biochemistry University o Oulu Oulu, Finland Adjunct Pro essor o Clinical Chemistry University o ampere ampere, Finland Disorders of Bone and Mineral Metabolism Norman B. Roberts, M.Sc., Ph.D., C.Chem. Consultant Clinical Scientist Department o Clinical Biochemistry T e Royal Liverpool and Broadgreen University Hospitals Honorary Reader, Clinical Chemistry T e University o Liverpool Liverpool, United Kingdom Vitamins, race Elements, and Nutritional Assessment Alan L. Rockwood, Ph.D., D.A.B.C.C. Scientif c Director or Mass Spectrometry ARUP Laboratories Pro essor (Clinical) o Pathology University o Utah School o Medicine Salt Lake City, Utah Mass Spectrometry T omas G. Rosano, Ph.D., D.A.B.F. ., D.A.B.C.C. Head o Clinical Laboratory Services Director o Clinical Chemistry and Forensic oxicology Albany Medical Center Hospital and College Albany, New Y ork Catecholamines and Serotonin Francois A. Rousseau, M.D., M.S., F.R.C.P.C. Head, Department o Medical Biology Faculty o Medicine University o Laval Quebec, Canada Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine David B. Sacks, M.D., Ch.B., F.R.C.Path. Adjunct Pro essor Department o Medicine Division o Endocrinology and Metabolism Georgetown University Washington, D.C. Carbohydrates; Diabetes Desmond Schatz, M.D. Pro essor and Associate Chairman Department o Pediatrics Division o Endocrinology Medical Director, Diabetes Center University o Florida Gainesville, Florida T yroid Disorders Emily I. Schindler, M.D., Ph.D. Resident Physician Department o Pathology and Immunology Barnes Jewish Hospital St. Louis, Missouri Electrolytes and Blood Gases; Physiology and Disorders of Water, Electrolyte, and Acid-Base Metabolism Mitchell G. Scott, Ph.D. Pro essor o Pathology and Immunology Co-Medical Director, Clinical Chemistry Division o Laboratory and Genomic Medicine Washington University School o Medicine St. Louis, Missouri Electrolytes and Blood Gases; Physiology and Disorders of Water, Electrolyte, and Acid-Base Metabolism Alan Shenkin, Ph.D., F.R.C.P., F.R.C.Path. Emeritus Pro essor Unit o Clinical Chemistry School o Clinical Sciences University o Liverpool Liverpool, United Kingdom Vitamins, race Elements, and Nutritional Assessment
  • 16. Contributors xii Nicholas E. Sherman, Ph.D. Research Associate Pro essor Director o Mass Spectrometry University o Virginia Charlottesville, Virginia Mass Spectrometry Christine L.H. Snozek, Ph.D., D.A.B.C.C. Assistant Pro essor Mayo Clinic College o Medicine Director o Chemistry, Collections/Processing, and Point-o -Care esting Department o Laboratory Medicine and Pathology Mayo Clinic in Arizona Scottsdale, Arizona T erapeutic Drugs and T eir Management Lori J. Sokoll, Ph.D., F.A.C.B. Associate Pro essor o Pathology, Oncology, and Urology Associate Director, Clinical Chemistry Division Department o Pathology Johns Hopkins Medical Institutions Baltimore, Maryland umor Markers and Cancer Genes Andrew St. John, Ph.D. ARC Consulting Mt. Lawley Western Australia, Australia Point-of-Care Instrumentation G. Russell Warnick, M.S., M.B.A. Executive Director Foundation or Health In ormation and echnology Chie Science O cer Health Diagnostic Laboratory Richmond, Virginia Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors James O. Westgard, Ph.D. Pro essor Department o Pathology and Laboratory Medicine University o Wisconsin Medical School Madison, Wisconsin Quality Management Sharon D. Whatley, Ph.D. Clinical Biochemist Medical Biochemistry Department University Hospital o Wales, Cardi , United Kingdom Porphyrins and Porphyrias Ronald J. Whitley, Ph.D., F.A.C.B., D.A.B.C.C. Pro essor Department o Pathology and Laboratory Medicine University o Kentucky Director o Clinical Chemistry, oxicology, and Core Laboratories University o Kentucky Medical Center College o Medicine Lexington, Kentucky Catecholamines and Serotonin William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P. Pro essor Departments o Pathology, Immunology & Laboratory Medicine, Pediatrics, and Molecular Genetics & Microbiology Principle Investigator, ype 1 Diabetes rialNet ICA Core Laboratory Director, UF Pathology Laboratories, Endocrine Autoantibody Laboratory University o Florida Gainesville, Florida Disorders of Bone and Mineral Metabolism; Disorders of the Pituitary; Disorders of the Adrenal Cortex; T yroid Disorders Carl . Wittwer, M.D., Ph.D. Pro essor o Pathology University o Utah School o Medicine Salt Lake City, Utah Nucleic Acid echniques and Applications; Genomes and Nucleic Acid Variations
  • 17. xiii As a practitioner and instructor o clinical chemistry or over 20 years, I have observed many innovative changes in the clinical laboratory, rom implementation o new analytical techniques to dependence on laboratory in ormatics to the inclusion o molecular testing and its unique practice stan- dards. I have worked with the editors and publishers o Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics as consulting editor or three editions and have ollowed each edition as they re ect the numerous advances in laboratory science. In the area o education, such updates are crucial or in orming students o what they should expect in their careers as pro essional laboratorians or as other practitioners in health care. As with previous editions, the seventh edition o Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics presents in ormation that today’ s clinical chemistry students and practicing laboratorians must know to succeed in this dis- cipline and in the contemporary world o pathology. T e true purpose o education must go beyond providing the knowledge necessary to be success ul in a particular eld. It must also stimulate and encourage students to investigate knowledge beyond that presented in the ormal classroom set- ting.T e highlyregarded authors o the seventh edition o Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics excel at presenting essential knowledge. T eir updates and re- visions o traditional topics and the addition o new chapters, such as “Pharmacogenetics” and “Genomes and Nucleic Acid Alterations,” provide interesting and indispensable material or the active learner. o inspire students to seek in ormation be- yond that provided in the various chapters, the seventh edition provides end-o -chapter multiple-choice questions that en- courage continued review and study. Updated websites within each chapter of er urther sources o data to increase under- standing o the subject matter. T ought-provoking gures that illustrate chapter concepts and innovative algorithms that pro- vide a unique way o examining diagnostic issues have been added to this edition. For both the educator and the student, improved and testable objectives have been designed and related est Bank questions have been added, revised, or modi ed. For the laboratory science student, the pro essional laboratorian, and the practicing pathologist, this textbook serves as an outstand- ing resource or (1) the study o basic laboratory operations, (2) understanding clinical chemistry analytes, and (3) com- prehending undamental pathophysiology. T e last chapter “Re erence In ormation or the Clinical Laboratory” provides an excellent source o re erence intervals or analytes o clini- cal relevance. As with previous editions o Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, this textbook provides something o interest or anyone who is involved in the eld o medical laboratory science. It is a privilege and an honor to have been invited to take part in the continuation o such a quality endeavor as this ex- ceptional textbook. o observe and comment on its continued growth and maturation is both rewarding and stimulating. I nd it truly ul lling to know that students, educators, manag- ers, and pathologists use this text as a primary resource in the classroom, laboratory, and clinic or in ormation regardingthe eld o clinical chemistry. Maintaining the highest standards o quality while providing crucial contemporary in ormation that is both concise and readable, this volume continues in the tradition o excellence set by previous editions o Tietz Funda- mentals of Clinical Chemistry and Molecular Diagnostics. Barbara G. Sawyer, Ph.D., M.L.S.(A.S.C.P.)CM , M.B.(A.S.C.P.)CM Professor, Clinical Laboratory Science/Molecular Pathology Foreword
  • 19. xv As the discipline o clinical laboratory science and medi- cine has evolved and expanded, each new edition o Tietz Fundamentals of Clinical Chemistry has been revised to re ect these changes. T e seventh edition o this series is no excep- tion, as we have made signi cant revisions in its ormat and content. First, re ecting the e ect that molecular diagnos- tics has had and continues to have on the practice o clinical chemistry and laboratory medicine, we have retitled the seventh edition as Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics. Consequently, chapters have been added on the topic o molecular diagnostics and many o the other updated chapters now include discussions o genetic testing and descriptions o the genetic basis o diseases. Second, 47 new authors along with 53 veterans rom the sixth edition have joined our company o subject-matter experts to revise and produce chapters that re ect the state- o -the-art in their respective elds. Consequently, this new edition covers many new topics and updates in ormation on older ones. With these changes, the seventh edition now contains 50 chapters that are grouped into sections entitled (I) Principleso LaboratoryMedicine,(II) Analytical echniques and Instrumentation, (III) Analytes, (IV) Pathophysiology, (V) Molecular Diagnostics, and (VI) Re erence In ormation. T ird, learning tools have been added or expanded. For ex- ample, a set o objectives and a list o keyterms and de nitions were included at the beginning o each chapter. (Note: in each chapter key terms are listed in alphabetical order in a bold red ont and again when each appears or the rst time in their respective chapter.) At the end o each chapter, a list o review questions has been added to assist students in the review o the salient points covered in each chapter. At the end o the book, we have combined the keywords and de nitions into a Glossary. O note, many o these key words and de nitions were obtained, in whole or in part, rom the 32nd edition o Dorland’ s Illustrated Medical Dictionary, with permission kindly granted by Elsevier. As with the sixth edition, we have relied on in ormation technology to prepare and produce the seventh edition. For example, each chapter was submitted and edited via Elsevier’ s “Electronic Manuscript Submission System.” In addition, many o the gures, especially those that included chemi- cal structures, were drawn or revised by Ed Ashwood using ChemWindows sof ware. T is resulted in a uni orm represen- tation o chemical structures and acilitated the integration o gures within the text while reducing errors. Readers will note that re erences to web-based sources o in ormation are ound throughout the text. o assist us in preparing the seventh edition, we again in- vited Barbara G. Sawyer, Ph.D., to join our editorial team as an educational consultant. Because o her experience with using Fundamentalsas a teaching text and her perspective as an edu- cator, Pro essor Sawyer’ s advice and assistance were again very use ul to us as we produced the seventh edition. We appreciate the opportunity provided us by Elsevier to prepare the seventh edition o Tietz Fundamentals of Clinical Chemistry. It has been an exciting, challenging, and educa- tional experience. We trust that this edition will live up to the reputation and success o its distinguished predecessors. We have enjoyed working with the team o dedicated authors that have spent many hours preparing comprehensive chapters that are authoritative and timely. We thank them sincerely and believe that they have enabled us to produce a textbook that is re ective o the diverse, technical, and practical nature o the current practice o clinical laboratory science and medicine. We have also bene ted rom and enjoyed working with the Elsevier sta , especially Sonya Seiga use, Executive Content Strategist;Ellen Wurm-Cutter, Content Development Manager; and Rachel E. McMullen and Andrea Campbell, Senior Project Managers.T eir patience, cooperation,advice,and pro essional dedication are grate ully acknowledged. Finally, we thank our valued colleague Ed Ashwood or his years o work as an editor o this book’ s predecessors. T e cur- rent product continues to bene t rom his manycontributions. Carl A. Burtis David E. Bruns Preface
  • 21. xvii P AR T I PRINCIPLES OF LABORATORY MEDICINE 1 Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine, 1 David E. Bruns, M.D., François A. Rousseau, M.D., and Carl A. Burtis, Ph.D. Laboratory Medicine, 1 Clinical Chemistry and Laboratory Medicine, 2 Molecular Diagnostics, 3 Ethical Issues in Laboratory Medicine, 3 Review Questions, 5 2 Selection and Analytical Evaluation of Meth- ods—With Statistical Techniques, 6 Kristian Linnet, M.D., Ph.D. and James C. Boyd, M.D. Method Selection, 7 Basic Statistics, 8 Basic Concepts in Relation to Analytical Methods, 11 Analytical Goals, 15 Method Comparison, 16 Monitoring Serial Results, 28 Traceability and Measurement Uncertainty, 28 So tware Packages, 30 Review Questions, 31 3 Clinical Evaluation of Methods, 33 Edward R. Ashwood, M.D. and David E. Bruns, M.D. Sensitivity and Speci city, 33 Receiver Operating Characteristic Plots, 34 Probabilistic Reasoning, 35 Prevalence, 35 Predictive Values, 35 Odds Ratio, 36 Likelihood Ratio, 36 Bayes’ Theorem, 36 Combination Testing, 37 Methods o Assessing Diagnostic Accuracy, 38 Review Questions, 38 4 Evidence-Based Laboratory Medicine, 40 Christopher P. Price, Ph.D., F.R.S.C., F.R.C.Path. Patrick M.M. Bossuyt, Ph.D., and David E. Bruns, M.D. Evidence-Based Medicine—What Is It?, 41 Evidence-Based Medicine and Laboratory Medicine, 42 In ormation Needs in Evidence-Based Laboratory Medicine, 43 Characterization o Diagnostic Accuracy Tests, 44 Outcomes Studies, 45 Systematic Reviews o Diagnostic Tests, 48 Economic Evaluations o Diagnostic Testing, 50 Clinical Practice Guidelines, 53 Clinical Audit, 56 Applying the Principles o Evidence-Based Laboratory Medicine in Routine Practice, 57 Review Questions, 58 5 Establishment and Use of Reference Values, 60 Gary L. Horowitz, M.D. Establishment o Re erence Values, 61 Use o Re erence Values, 67 Review Questions, 70 6 Specimen Collection, Processing, and Other Preanalytical Variables, 72 Doris M. Haverstick, Ph.D., D.A.B.C.C., and Amy R. Groszbach, M.E.D., M.L. ., M.B.(A.S.C.P.)CM Types o Specimens, 73 Handling o Specimens or Analysis, 81 Review Questions, 88 7 Quality Management, 90 George G. Klee, M.D., Ph.D. and JamesO. Westgard, Ph.D. Fundamentals o Total Quality Management, 91 Implementing TQM, 93 Personnel Competency and Training, 94 The Total Testing Process, 94 Control o Preanalytical Variables, 95 Control o Analytical Variables, 96 External Quality Assessment and Pro ciency Testing Programs, 102 Contents
  • 22. Contents xviii New Quality Initiatives, 103 Review Questions, 105 8 Principles of Basic Techniques and Laboratory Safety, 107 Stanley F. Lo, Ph.D., D.A.B.C.C., F.A.C.B. Concept o Solute and Solvent, 108 Units o Measurement, 109 Chemicals, 111 Re erence Materials, 112 Basic Techniques and Procedures, 113 Review Questions, 127 P A R T II ANALYTICAL TECHNIQUES AND INSTRUMENTATION 9 Optical Techniques, 129 L.J. Kricka, D.Phil., F.A.C.B., C.Chem., F.R.S.C., F.R.C.Path. and Jason Y . Park, M.D., Ph.D., F.C.A.P. Photometry and Spectrophotometry, 131 Instrumentation, 133 Ref ectance Photometry, 138 Atomic Absorption Spectrophotometry, 138 Fluorometry, 139 Phosphorimetry, 146 Luminometry, 146 Nephelometry and Turbidimetry, 147 Review Questions, 149 10 Electrochemistry and Chemical Sensors, 151 Paul D’Orazio, Ph.D. and Mark E. Meyerhof , Ph.D. Potentiometry, 152 Voltammetry/Amperometry, 158 Conductometry, 162 Coulometry, 163 Optical Chemical Sensors, 163 Biosensors, 164 Review Questions, 169 11 Electrophoresis, 171 Lindsay A.L. Bazydlo, Ph.D. and James P. Landers, Ph.D. Basic Concepts and De nitions, 172 Theory o Electrophoresis, 172 Description o Technique, 172 Types o Electrophoresis, 175 Technical Considerations, 180 Review Questions, 181 12 Chromatography, 183 Glen L. Hortin, M.D., Ph.D. and Carl A. Burtis, Ph.D. Basic Concepts, 184 Separation Mechanisms, 187 Planar Chromatography, 189 Column Chromatography, 190 Qualitative and Quantitative Analyses, 198 Review Questions, 200 13 Mass Spectrometry, 202 Alan L. Rockwood, Ph.D., D.A.B.C.C., T omas M. Annesley, Ph.D., and Nicholas E. Sherman, Ph.D. Basic Concepts and De nitions, 203 Instrumentation, 205 Clinical Applications, 213 Review Questions, 214 14 Enzyme and Rate Analyses, 216 Renze Bais, Ph.D., F.F.Sc. (R.C.P.A.) and Mauro Pan- teghini, M.D. Basic Principles, 217 Enzyme Kinetics, 223 Analytical Enzymology, 229 Review Questions, 234 15 Immunochemical Techniques, 236 L.J. Kricka, D.Phil., F.A.C.B., C.Chem., F.R.S.C., F.R.C.Path. and J.Y . Park, M.D., Ph.D., F.C.A.P. Basic Concepts and De nitions, 237 Antigen-Antibody Binding, 238 Qualitative Methods, 240 Quantitative Methods, 242 Other Immunochemical Techniques, 252 Review Questions, 252 16 Automation, 254 James C. Boyd, M.D. and Charles D. Hawker, Ph.D., M.B.A., F.A.C.B. Basic Concepts, 255 Automation o Analytical Processes, 255 Integrated Automation or the Clinical Labora- tory, 263 Practical Considerations, 267 Other Areas o Automation, 269 Review Questions, 270 17 Point-of-Care Instrumentation, 272 Christopher P. Price, Ph.D., F.R.S.C., F.R.C.Path. and Andrew St. John, Ph.D., F.F.Sc. (R.C.P.A.) Analytical and Technological Considerations, 273 Implementation and Management Consider- ations, 280 Review Questions, 284 P A R T III ANALYTES 18 Amino Acids, Peptides, and Proteins, 286 Glen L. Hortin, M.D., Ph.D. Amino Acids, 287 Peptides and Proteins, 292 Analysis o Proteins, 293 Plasma and Serum Proteins, 299 Review Questions, 317
  • 23. Contents xix 19 Serum Enzymes, 318 Mauro Panteghini, M.D. and Renze Bais, Ph.D., F.F.Sc. (R.C.P.A.) Basic Concepts, 319 Muscle Enzymes, 319 Liver Enzymes, 322 Pancreatic Enzymes, 328 Other Clinically Important Enzymes, 331 Enzymes as Cardiovascular Risk Markers, 334 Review Questions, 335 20 Tumor Markers and Cancer Genes, 337 Lori J. Sokoll, Ph.D., F.A.C.B., Alex J. Rai, Ph.D., D.A.B.C.C., F.A.C.B., and Daniel W. Chan, Ph.D., D.A.B.C.C., F.A.C.B. Cancer, 339 Clinical Applications, 339 Evaluating Clinical Utility, 341 Clinical Guidelines, 342 Analytical Methods, 342 Enzymes, 342 Hormones, 347 Onco etal Antigens, 349 Cytokeratins, 351 Carbohydrate Markers, 352 Blood Group Antigens, 354 Proteins, 355 Receptors, 357 Circulating Tumor, 358 Genetic and Molecular Markers, 358 Other Molecular Tests, 362 Microarray-Based Markers, 362 Review Questions, 363 21 Kidney Function Tests—Creatinine, Urea, and Uric Acid, 364 Edmund J. Lamb, Ph.D., F.R.C.Path. and Christopher P. Price, Ph.D., F.R.C.Path. Creatinine, 365 Urea, 368 Uric Acid, 370 Review Questions, 374 22 Carbohydrates, 376 David B. Sacks, M.D., Ch.B., F.R.C.Path. Chemistry o Carbohydrates, 377 Biochemistry and Physiology, 379 Analytical Methodology, 382 Review Questions, 387 23 Lipids, Lipoproteins, Apolipoproteins, and Other Cardiac Risk Factors, 388 Alan . Remaley, M.D., Ph.D., Nader Ri ai, Ph.D., and G. Russell Warnick, M.S., M.B.A. Basic Lipids, 389 Lipoproteins, 397 Apolipoproteins, 399 Metabolism o Lipoproteins, 399 Clinical Signi cance, 401 Analysis o Lipids, Lipoproteins, and Apolipo- proteins, 407 Advanced Testing or Risk o Cardiovascular Disease, 409 Review Questions, 410 24 Electrolytes and Blood Gases, 412 Mitchell G. Scott, Ph.D., Vicky A. LeGrys, Ph.D., Dr.A., M. .(A.S.C.P.), C.L.S.(N.C.A.), and Emily I. Schindler, M.D., Ph.D. Electrolytes, 413 Principles o Osmotic Pressure and Osmosis, 420 Blood Gases and pH, 421 Review Questions, 428 25 Hormones, 430 Michael Kleerekoper, M.D., F.A.C.B., F.A.C.P., M.A.C.E. Classi cation, 431 Release and Action o Hormones, 435 Role o Hormone Receptors, 436 Postreceptor Actions o Hormones, 437 Measurements o Hormones and Related Ana- lytes, 439 Review Questions, 441 26 Catecholamines and Serotonin, 442 Graeme Eisenho er, Ph.D., T omas G. Rosano, Ph.D., D.A.B.F. ., D.A.B.C.C., and Ronald J. Whitley, Ph.D., F.A.C.B., D.A.B.C.C. Chemistry, Biosynthesis, Release, and Me- tabolism, 444 Physiology o Catecholamine and Serotonin Systems, 446 Clinical Applications, 449 Analytical Methodology, 453 Review Questions, 458 27 Vitamins, Trace Elements, and Nutritional As- sessment, 459 Alan Shenkin, Ph.D., F.R.C.P., F.R.C.Path. and Norman B. Roberts, M.Sc., Ph.D., C.Chem. Vitamins, 461 Trace Elements, 482 Review Questions, 498 28 Hemoglobin, Iron, and Bilirubin, 499 re or Higgins, M.Sc., F.C.A.C.B., John H. Eck eldt, M.D., Ph.D., James C. Barton, M.D., and Basil . Doumas, Ph.D. Hemoglobin, 501 Iron, 508 Bilirubin, 513 Review Questions, 519
  • 24. Contents xx 29 Porphyrins and Porphyrias, 522 Michael N. Badminton, M.B.Ch.B., Ph.D., F.R.C.Path., Sharon D. Whatley, Ph.D., Allan C. Deacon, Ph.D., F.R.C.Path., and George H. Elder, M.D., F.R.C.P., F.R.C.Path. Porphyrin and Heme Chemistry, 523 Primary Porphyrin Disorders, 527 Abnormalities o Porphyrin Metabolism not Caused by Porphyria, 529 Laboratory Diagnosis o Porphyria, 530 Analytical Methods, 533 Review Questions, 534 30 Therapeutic Drugs and Their Management, 536 Christine L.H. Snozek, Ph.D., D.A.B.C.C. and Gwendo- lyn A. McMillin, Ph.D., D.A.B.C.C.(C.C., .C.) Basic Concepts, 537 Clinical and Analytical Considerations, 543 Speci c Drug Groups, 545 Review Questions, 558 31 Clinical Toxicology, 559 Loralie Langman, Ph.D., F.C.A.C.B., D.A.B.C.C.(C.C., M.B., .C.), D.A.B.F. ., Laura K. Bechtel, Ph.D., D.A.B.C.C., and Christopher P. Holstege, M.D. Basic In ormation, 561 Screening Procedures or Detection o Drugs, 562 Pharmacology and Analysis o Speci c Drugs and Toxic Agents, 564 Agents That Cause Cellular Hypoxia, 565 Alcohols, 566 Analgesics (Nonprescription), 569 Agents Related to Anticholinergic Toxidrome, 570 Agents Related to Cholinergic Toxidrome, 572 Drugs o Abuse, 574 Drugs Used in Sexual Assault, 586 Review Questions, 590 32 Toxic Metals, 592 T omas P. Moyer, Ph.D. Assessment o Metal Poisoning, 593 Speci c Metals, 594 Review Questions, 606 PART IV PATHOPHYSIOLOGY 33 Diabetes, 608 David B. Sacks, M.B., Ch.B., F.R.C.Path. Classi cation, 610 Hormones that Regulate Blood Glucose Concentration, 611 Measurement o Insulin, Proinsulin, C-Peptide, and Glucagon, 614 Pathogenesis o Type 1 Diabetes Mellitus, 616 Pathogenesis o Type 2 Diabetes Mellitus, 617 Diagnosis o Diabetes, 618 Chronic Complications o Diabetes Mellitus, 620 Role o the Clinical Laboratory in Diabetes Mellitus, 620 Sel -Monitoring o Blood Glucose, 621 Alternatives to Meters or Monitoring o Blood Glucose, 623 Ketone Bodies, 623 Glycated Proteins, 625 Urinary Albumin Excretion, 629 Review Questions, 630 34 Cardiovascular Disease, 632 Fred S. Apple, Ph.D., Jens Peter Goetze, M.D., D.M.Sc., and Allan S. Jaf e, M.D. Anatomy and Physiology o the Heart, 633 Cardiac Disease, 635 Cardiac Biomarkers, 638 Review Questions, 649 35 Kidney Disease, 651 Michael P. Delaney, B.Sc., M.D., F.R.C.P., Christopher P. Price, Ph.D., F.R.S.C., F.R.C.Path. and Edmund J. Lamb, Ph.D., F.R.C.Path. Anatomy, 653 Kidney Function, 655 Kidney Physiology, 658 Pathophysiology o Kidney Disease, 663 Other Diseases o the Kidney, 671 Renal Replacement Therapy, 675 Review Questions, 678 36 Physiology and Disorders of Water, Electrolyte, and Acid-Base Metabolism, 680 Emily I. Schindler, M.D., Ph.D. and Mitchell G. Scott, Ph.D. Total Body Water—Volume and Distribution, 681 Electrolytes, 682 Acid-Base Physiology, 688 Conditions Associated with Abnormal Acid-Base Status and Abnormal Electrolyte Composition o the Blood, 692 Review Questions, 698 37 Liver Disease, 700 D. Robert Du our, M.D. Anatomy o the Liver, 702 Biochemical Functions o the Liver, 704 Clinical Mani estations o Liver Disease, 707 Diseases o the Liver, 710 Diagnostic Strategy, 720 Review Questions, 722
  • 25. Contents xxi 38 Gastrointestinal and Pancreatic Diseases, 724 Peter G. Hill, Ph.D., F.R.C.Path. Anatomy, 725 The Digestive Process, 726 Gastrointestinal Regulatory Peptides, 728 Stomach, Intestinal, and Pancreatic Diseases and Disorders, 730 Review Questions, 740 39 Disorders of Bone and Mineral Metabolism, 741 Juha Risteli, M.D., Ph.D., F.E.B.M.B., William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P., Michael Kleerekoper, M.D., F.A.C.B., F.A.C.P., M.A.C.E., and Leila Risteli, M.D., Ph.D., M.A., F.E.B.M.B. Overview o Bone and Mineral Metabolism, 743 Calcium, 744 Phosphate, 749 Magnesium, 751 Hormones Regulating Mineral Metabolism, 753 Integrated Control o Mineral Metabolism, 760 Biochemical Markers o Bone Turnover, 761 Metabolic Bone Diseases, 765 Review Questions, 767 40 Disorders of the Pituitary, 769 Ishwarlal Jialal, M.D., Ph.D., F.R.C.Path.(London), D.A.B.C.C., William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P., and Roger L. Berthol , Ph.D. Hypothalamic Regulation, 772 Hormones o the Adenohypophysis, 772 Hormones o the Neurohypophysis, 779 Assessment o Anterior Pituitary Lobe Reserve, 782 Review Questions, 783 41 Disorders of the Adrenal Cortex, 785 Roger L. Berthol , Ph.D., Ishwarlal Jialal, M.D., Ph.D., F.R.C.Path.(London), D.A.B.C.C., and William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P. General Steroid Chemistry, 786 Adrenocortical Steroids, 788 Dynamic Tests o Adrenal Function, 793 Disorders o the Adrenal Cortex, 795 Laboratory Evaluation o Adrenocortical Function, 800 Review Questions, 805 42 Thyroid Disorders, 806 William E. Winter, M.D., D.A.B.C.C., F.A.C.B., F.C.A.P., Desmond Schatz, M.D., and Roger L. Berthol , Ph.D. Thyroid Hormones, 808 Thyroid Disorders, 812 Analytical Methodology, 818 Review Questions, 822 43 Reproduction-Related Disorders, 824 Mari L. DeMarco, Ph.D. and Ann M. Gronowski, Ph.D. Male Reproductive Biology, 826 Female Reproductive Biology, 830 In ertility, 841 Analytical Methodology, 843 Review Questions, 846 44 Pregnancy and Prenatal Testing, 848 David G. Grenache, Ph.D., M. . (A.S.C.P.), D.A.B.C.C., F.A.C.B. and Geralyn Lambert-Messerlian, Ph.D., F.A.C.B. Human Pregnancy, 850 Maternal Adaptation, 853 Functional Development o the Fetus, 854 Maternal and Fetal Health Assessment, 855 Complications o Pregnancy, 856 Prenatal Screening or Fetal De ects, 859 Analytical Methodology, 863 Review Questions, 868 45 Newborn Screening and Inborn Errors of Metabolism, 870 Marzia Pasquali, Ph.D., F.A.C.M.G. and Nicola Longo, M.D., Ph.D., F.A.C.M.G. Inheritance Pattern o Metabolic Disorders, 872 Newborn Screening, 872 Inborn Errors o Metabolism, 873 Diagnostic Tests or Inherited Disorders o Metabolism, 882 Review Questions, 883 46 Pharmacogenetics, 885 Gwendolyn A. McMillin, Ph.D., D.A.B.C.C. (C.C., .C.) De ning Pharmacogenetic Targets, 887 Approaches to Pharmacogenetic Testing, 887 Clinical Applications o Pharmacogenetic Test- ing, 888 Drug Metabolism and Pharmacogenomics, 889 Review Questions, 897 P A R T V MOLECULAR DIAGNOSTICS 47 Principles of Molecular Biology, 899 Y . M. Dennis Lo, M.A., D.M., D.Phil., F.R.C.P., F.R.C.Path., F.R.S. and Rossa W. K. Chiu, M.B.B.S., Ph.D., F.R.C.P.A., F.H.K.A.M. (Pathology) Landmark Developments in Genetics and Molecular Diagnostics, 901 The Essentials, 902 Nucleic Acid Structure and Organization, 902 Nucleic Acid Physiology and Functional Regu- lation, 906 Genetics and Epigenetics, 909 Beyond the Nuclear Genome, 911 Understanding Our Genome, 912 Review Questions, 913
  • 26. Contents xxii 48 Nucleic Acid Techniques and Applications, 915 Carl . Wittwer, M.D., Ph.D. and Noriko Kusukawa, Ph.D. Nucleic Acid Enzymes, 918 Ampli cation Techniques, 919 Detection Techniques, 924 Discrimination Techniques, 924 Review Questions, 944 49 Genomes and Nucleic Acid Variations, 946 Carl . Wittwer, M.D., Ph.D. and Noriko Kusukawa, Ph.D. Genomes and Nucleic Acid Variations, 947 Review Questions, 960 P A R T VI REFERENCE INFORMATION 50 Reference Information for the Clinical Labora- tory, 951 Gwendolyn A. McMillin, Ph.D., D.A.B.C.C. (C.C., .C.), Carl A. Burtis, Ph.D., and David E. Bruns, M.D. Re erence Intervals and Values, 952 Therapeutic and Toxic Levels o Drugs, 982 Critical Values, 993
  • 27. 1 P A R T I Principles of Laboratory Medicine C H A P TE R 1 Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine David E. Bruns, M.D., Francois A. Rousseau, M.D., and Carl A. Burtis, Ph.D. Ob je c tive s 1. De ne the ollowing terms: Core laboratory Molecular diagnostics Ethics Pharmacogenetics Laboratorymedicine 2. List and explain sixreasons or per orming a laboratorytest. 3. Describe the eld o laboratory medicine, including subdisci- plines, in ormation handling, and ethical issues. 4. State the contribution o epidemiology to the eld o clinical chemistry. 5. State the applications o molecular diagnostics in laboratory medicine. 6. List and explain ve ethical issues that con ront laboratorians; state the criticalimportance o maintaining con dentialityin the laboratory. 7. Evaluate a possible con dentiality or confict o interest issue and determine whether it is an ethics violation. Ke y Wo rd s a n d De fin itio n s Core laboratory Alaboratory that provides all o the high-volume and emergencytesting in manyhospitals. Ethics Rules or standards governing the conduct o an individual or the members o a pro ession. Laboratory medicine Acomponent o laboratory science that is involved in the selection, provision, and interpretation o diag- nostic testing o individual specimens. Laboratory testing A process conducted in a clinical laboratory to rule in or rule out a diagnosis, to select and monitor disease treatment, to provide a prognosis, to screen or a disease, or to determine the severityo andmonitora physiologicaldisturbance. Molecular diagnostics U se o molecular biologytechniques or the purposes o prevention, diagnosis, and ollow-up or prognosis o disease;andselection,optimization,andmonitoringo therapies. In this chapter, we begin with a general discussion to intro- duce the eld o laboratory medicine and the disciplines o clinical chemistry (or clinical biochemistry) and molecular diagnostics. T is will include a discussion o the meaning o the term laboratory medicine and the relationships among (1) clinical chemistry, (2) molecular diagnostics, (3) labora- tory medicine, and (4) evidence-based laboratory medicine. T e concepts introduced in this chapter are developed in the remaining chapters o this book. T e chapter concludes with a discussion on the ethical issues that clinical chemists/biochemists ace in the practice o their pro ession and issues that they will ace in the uture. Laboratory Medicine T e term laboratorymedicine re ers to the discipline involved in the (1) selection, (2) provision, and (3) interpretation o diagnostic testing that uses primarily samples rom patients. T is discipline includes (1) research, (2) administration, (3) teaching activities, and (4) clinical service. esting in labo- ratory medicine may be directed at (1) con rming a clinical suspicion,which mayinclude making,or rulingin,a diagnosis, (2) excluding, or ruling out, a diagnosis, (3) assisting in selec- tion, optimization, and monitoring o treatment, (4) providing a prognosis, (5) screening or disease in the absence o clinical
  • 28. PART I Principles of Laboratory Medicine 2 signs or symptoms, and (6) establishing and monitoring the severity o a physiological disturbance (Box 1-1). T e eld o laboratory medicine includes clinical chem- istry and its traditional subdisciplines (including toxicology and drug monitoring, endocrine and organ unction test- ing, and “biochemical” and “molecular” genetics) and areas such as microbiology, hematology, hemostasis and throm- bosis, blood banking (trans usion medicine), immunology, and identity testing (Box 1-2). In some parts o the world, laboratory medicine also encompasses cytology and anatomic pathology (histopathology). In recent years, molecular diag- nostics has become an increasingly important part o all o the specialties o laboratory medicine. In ormation management and interpretation (including laboratory in ormatics) are key aspects o the laboratory medicine service, as are activities concerned with maintaining quality, such as (1) quality con- trol, (2) pro ciency testing, (3) audit, (4) benchmarking, and (5) clinical governance. Closer links with patients are increas- ingly attained through the use o telemedicine and tele-health- care, which includes acets o laboratory medicine such as (1) analytical testing, (2) the use o clinical decision support systems, and (3) in ormatics. Clinical Chemistry and Laboratory Medicine T e ties between clinical chemistry and other areas o labora- tory medicine have deep roots. Individuals working primar- ily in the area o clinical chemistry/biochemistry have devel- oped tools and methods that have become part o the abric o laboratory medicine beyond the clinical chemistry laboratory. Examples include (1) the theory and practice o re erence in- tervals (see Chapter 5), (2) the use o both (internal) quality control and pro ciency testing (see Chapter 7), (3) the intro- duction o automation into the clinical laboratory (see Chapter 16), and (4) concepts o diagnostic testing (see Chapters 3 and 4). From physician and patient perspectives, no distinction is evident among these specialties, and invariably the repertoire o more than one specialty will be called upon when a clini- cal decision is made. Examples o clinical scenarios that require tests rom multiple laboratory areas include the diagnosis and management o many diseases and the management o patients in intensive care (see Chapters 33 through 45). Boundaries between and among the parts o the clini- cal laboratory have become more blurred with increasing emphasis on the use o chemical and “molecular” (nucleic acid) testing. Molecular diagnostic testing has evolved beyond human genetic testing—an area in which clinical chemists have long been active. Now, clinical chemists in “molecular” laboratories contribute their expertise in laboratory medicine to in ectious disease testing, cancer diagnostics, and identity testing—activities that ormerly were associated primarily or solely with, respectively, clinical microbiology, hematology, and blood bank laboratories. Success ul contributions by clin- ical chemists to these areas require an understanding o the principles o laboratory medicine and close collaboration with clinical microbiologists, hematologists, and others who have specialized expertise in those areas o laboratory medicine. T e relationship between the clinical chemist and labora- tory medicine has evolved urther with the advent o “core” laboratories. T ese laboratories provide all o the high- volume and emergency testing in many hospitals. T eir e - cient and reliable operation depends on automation (see Chapter 16), computers, and high levels o quality control and quality management (see Chapter 7). Clinical chemists, who have long been active in these areas, have assumed increasing responsibility in core laboratories and thus have become more involved in areas such as hematology, coagulation, urinalysis, and even microbiology. T us a new type o “clinical chem- ist” has emerged, and again the unctions require a broader knowledge o laboratory medicine and greater collaboration with other specialists. A virtual merger o clinical chemistryand laboratorymedi- cine has been suggested in many ways. For example, journals in the eld o clinical chemistry publish articles in all o the areaso laboratorymedicine.T ecurrent logo o the American Association or Clinical Chemistry reads, “ AACC—Improving Healthcare through Laboratory Medicine.” Moreover, the BOX 1-1 Uses of Testing in the Clinical Laboratory • Con rminga clinicalsuspicion(whichcouldinclude makinga diagnosis) • Excluding a diagnosis • A ssisting in selection, optimization, and monitoring o treatment • Providing a prognosis • Screening or disease in the absence o clinical signs or symptoms • Establishing and monitoring the severityo a physiologicaldisturbance BOX 1-2 Disciplines of the Modern-Day Clinical Laboratory • BiochemicalGenetics • Cancer Diagnostics • ClinicalChemistry/Biochemistry • ClinicalHematology • ClinicalImmunology • Cytogenetics • Drug M onitoring • EndocrinologyT esting • Hemostasis/Thrombosis (Coagulation)T esting • IdentityT esting • In ectious Disease T esting • In ormationT echnology • LaboratoryM anagement • M icrobiology • M olecular Cytogenetics • M olecular Diagnostics • Nutrition • Organ T ransplantation • Organ Function T esting • Pharmacogenetics • Proteomics • QualityM anagement • T oxicology • T race Elements • T rans usion M edicine (Blood Banking)
  • 29. CHAPTER 1 Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine 3 International Federation o Clinical Chemistry Societies is now called the International Federation o Clinical Chemistry and Laboratory Medicine (IFCC). Being active in the eld o laboratory medicine today requires, more o en than not, amiliarity with core concepts in several i not all o the sub- disciplines o the eld. During the past two decades, the eld o clinical chemistry has been pro oundly in uenced by new activities in the elds o clinical epidemiology and evidence-based medicine (see Chapter 4). Clinical epidemiologists have developed study designs to quanti y the diagnostic accuracy (as opposed to analytical accuracy) o tests developed in laboratory medicine (see Chapter 3). Moreover, they have introduced methods that are used to evaluate the ef ects and value o laboratory testing in healthcare (see Chapter 2). T ese developments are expected to play an increasing role in the selection and inter- pretation o tests. T us Chapter 4 o this book is devoted to evidence-based laboratory medicine. Molecular Diagnostics Molecular diagnostics is de ned as the use o the techniques o molecular biology or the purpose o prevention, diagnosis, ollow-up, or prognosis o disease. Molecular diagnostics has impacted all elds o laboratory medicine and has delivered several new diagnostic tools o proven clinical utility. A er the discovery o DNA as the repository o genetic in ormation in the 1950s, the development o molecular biology methods to studyDNAand RNA in the 1970s and 1980s, and the invention o the polymerase chain reaction (PCR) in 1985, analysis o nucleic acids and molecular biology methods have been used to decipher many biological processes o the living cell (see Chapters 46 to 49) in normal and disease states. T ese dis- coveries naturally led to the development o the discipline o molecular diagnostics, which entered the realm o laboratory medicine in multiple orms and in multiple elds. Molecular diagnostics has been applied to the study o the constitutive genome (e.g., inherited diseases, histocompatibility, identity assessment, pharmacogenetics; see Chapter 46) and to the study o acquired states (e.g., in ectious diseases, gra ing, and pregnancy). Molecular diagnostic methods can be qualitative or quantitative in nature, depending on the clinical need. T e eld o molecular diagnostics is characterized by very rapidly evolving technology (as the result o massive invest- ments in the human genome project and endeavors that ol- lowed), as well as by a rapidly increasing variety o potential clinical applications. O note, the advent o massively parallel nucleic acid sequencing is opening a wide spectrum o poten- tial new diagnostic applications, where tens to hundreds o millions o dif erent molecules are characterized and quanti- ed in a single experiment and supported by high throughput clinical bioin ormatic data analyses. Chapters 47, 48, and 49 provide an overview, respectively, o the Principles o Molecu- lar Biology, Nucleic Acid echniques and Applications, and Genome and Nucleic Acid Alterations. One eld in which molecular diagnostics has made a signi - icant impact is the studyo hematopoietic malignancies such as malignant lymphomas and leukemias. Easy access to malig- nant cells through a blood or bone marrow sample allowed the development o molecular biomarkers to re ne the diagnosis o such tumors. T ese include genetic rearrangements that are speci c to certain types o malignancies and are associ- ated with the aggressiveness and prognosis o the malignancy and, hence, are use ul tools or orienting treatment. Further, once the molecular signature o the patient’ s tumor has been identi ed, quantitative assays allow monitoring o response to therapy and aid in detection o residual disease in the event o a relapse and con rmation o durable remissions. Pharmacogenetics (see Chapter 46), or the study o varia- tion in drug metabolism between individuals, has been a eld o intensive work and increasing interest because studying the genomic DNA rom a patient is simpler than measuring the activity o enzymes in tissues that are not easily accessible but are involved in drug activation and metabolism. Apart rom the studyo tissues and nucleated cells, molecu- lar diagnostics has been applied to the study o plasma nucleic acids (or circulating nucleic acids; see Chapter 47). Plasma nucleic acid analysis has been made possible by the discovery that cells in the body release DNA and RNA into the extra- cellular compartment and ultimately into the bloodstream, where they can be detected and analyzed. Because o their short hal -li e in the circulation (less than 24 hours), plasma nucleic acids provide a measure o processes that are ongo- ing at the time o blood sampling. Such processes include the presence o nucleic acids rom abnormal tissue (tumor nucleic acids) or the existence o nonhost nucleic acids (microor- ganisms, gra –donor, and the etus during pregnancy). It is expected that molecular diagnostic analysis o plasma nucleic acids will enter routine clinical practice or various indications with the appearance o a high-quality evidence base or their clinical utility. Ethical Issues in Laboratory Medicine As in other branches o medicine, practitioners in laboratory medicine are aced with ethical issues, o en on a dailybasis;ex- amples are listed in Box 1-3. T e de nition o ethics varies, but in this chapter, the ollowing de nition is relevant: “T e rules or standards governing the conduct o an individual or the members o a pro ession (e.g., laboratory medicine).” Speci c ethical issues that pertain to the practice o laboratory medi- cine include but are not limited to (1) con dentiality o genetic in ormation and patient medical in ormation, (2) allocation BOX 1-3 Ethical Issues in Clinical Chemistry and Molecular Diagnostics • Con dentialityo genetic in ormation • Con dentialityo patient medicalin ormation • A llocation o resources • Codes o conduct • Publishing issues • Confict o interest
  • 30. PART I Principles of Laboratory Medicine 4 o healthcare resources, (3) codes o conduct, (4) publishing issues, and (5) con ict o interest. Con dentiality o Genetic In ormation Prominent in the news in the rst and second decades o this millennium has been the issue o con dentiality o genetic in ormation. Legislation was considered necessary to prevent denial o health insurance or employment to people ound by DNA testing to be at risk o disease. Less appreciated is the act that the issue o con dentiality o clinical laboratory data pre- dated DNA testing. In act, manynon-DNA tests, old and new, also carry in ormation about risks o illness and death. Clini- cal laboratorians have long been responsible or maintaining the con dentiality o all laboratory results—a situation made even more critical with the advent o increasingly power ul genetic testing. Con dentiality o Patient Medical In ormation Because new medical tests are constantly needed, laboratory physicians and scientists spend a great deal o time and ef ort developing new diagnostic tests or evaluating them or use in a speci c setting. T is process requires use o patient samples and may involve use o patient medical in ormation.3 Ethical judgments are required regarding the type o in ormed con- sent that is needed rom patients or use o their samples and clinical in ormation. Clinical laboratory physicians and scien- tists o en serve on institutional review boards that examine proposed research on human subjects. In these discussions, ethical concepts such as equipoise and con dentiality are central to decision making. Allocation o Healthcare Resources Because resources are nite,clinicallaboratorians must make ethically responsible decisions about allocation o resources in the clinical laboratory and beyond. When a trade-of exists between cost and quality (o testing reagents or analyz- ers, or example), ethical issues may need to be considered: What is best or patients generally? How can the most good be done with the available resources? Busines s Ethics For laboratorians in business, the newly appreciated area o business ethics comes into play. One example, recently epito- mized by scandals associated with names such as Madof and Enron, involves the area o accounting—a human endeavor that in the public mind had not been much associated with concerns about ethics. Codes o Conduct Most pro essional organizations publish a Code o Conduct that requires adherence by their members. For example, the American Association or ClinicalChemistry(AACC)haspub- lished Ethical Guidelines (http://www.aacc.org/about/ethics/ Pages/de ault.aspx#; accessed June 26, 2013) that require AACC members to endorse principles o ethical conduct in their pro essional activities, including (1) selection and per- ormance o clinical procedures, (2) research and development, (3) teaching, (4) management, (5) administration, and (6) oth- er orms o pro essional service. Publishing Iss ues Publication o documents having high scienti c integrity de- pends on authors, editors, and reviewers all working in con- cert in an environment governed by high ethical standards.2 Authors are responsible or honest and complete report- ing o original data produced in ethically conducted research studies. Practices such as raud, plagiarism, and alsi cation or abrication o data are unacceptable! T e International Com- mittee o Medical Journal Editors (ICMJE)7 and the Commit- tee on Publication Ethics (COPE)5 have published policies that address such behavior. Other practices to be avoided include redundant publication, and inappropriate credit or author- ship; in addition, ethical policies require that actors that might in uence the interpretation o a study must be revealed. Most journals now have con ict o interest policies or both authors and journal editors. For example, Clinical Chemistry requires that authors complete a ull disclosure orm upon manuscript submission. Annually, the Editor and Associate Editors are also required to complete such a orm (http://www. clinchem.org/;accessed June 26, 2013). Conf ict o Interes t Concern has been raised over the interrelationships between practitioners in the medical eld and commercial suppliers o drugs, devices, equipment, etc., to the medical pro ession.8 T ese concerns led the National Institutes o Health (NIH) in 1995 to require o cial institutional review o nancial disclo- sure by researchers and management o situations in which disclosure indicates potential con ict o interest and/or con ict o ef ort in research. In 2009, the Institute o Medicine (IOM) issued a report6 that questioned inappropriate relationships between pharmaceutical and device companies and physicians and other healthcare pro essionals.8 Similarly, the relationships between clinical laboratorians and manu acturers and provid- ers o diagnostic equipment and supplies have been scrutinized. As a consequence o these concerns and as a result o the enactment o various laws designed to prevent raud, abuse, and waste in Medicare, Medicaid, and other ederal programs, pro essional organizations that represent manu acturers o in vitro diagnostics (IVD) and other device and healthcare companies have published Codes o Ethics. For example, the Advanced Medical echnology Association (AdvaMed) has revised and published its Code o Ethics that became ef ective July 1, 2009.1 opics discussed in this revised Code include (1) gi s and entertainment, (2) consulting arrangements and royalties, (3) reimbursement or testing, and (4) education. Similarly, the European Diagnostic Manu acturers Association (EDMA) has published its Code o Ethics.4 In Part A o this document, topics discussed include (1) member-sponsored product training and education, (2) supporting third-party educational con erences, (3) sales and promotional meetings, (4) nancial arrangements or consultants (5) gi s, (6) provi- sion o reimbursements and other economic in ormation, and (7) donations or charitable and philanthropic purposes.
  • 31. CHAPTER 1 Clinical Chemistry, Molecular Diagnostics, and Laboratory Medicine 5 Both documents address demands rom regulators while nur- turing the unique role that laboratorians and other healthcare pro essionals play in developing and re ning new technology.8 In closing, it is our opinion that practitioners o clinical chemistry, molecular diagnostics, and laboratory medicine have be ore them a uture ull o promises and challenges. New insight into disease and its treatment is exploding, and these insights are based in sciences that are at the heart o the clinical laboratory. T e clinical laboratory is the place o translation o these insights into ef ective healthcare. We honor the impor- tant role o ethical laboratory pro essionals in these ef orts and have endeavored to provide in this book chapters prepared by expert authors that help to de ne the evidence base and the knowledge base o the pro ession. Review Questions 1. T e clinical laboratory discipline that is used most o en to assess inherited disease through study o the constitutive genome is: a. trans usion services. b. clinical chemistry. c. molecular diagnostics. d. hematology. 2. T e study o the genetic variation between individuals in their ability to metabolize drugs is re erred to as: a. pharmacogenetics. b. molecular diagnostics. c. clinical chemistry. d. epidemiology. 3. When a practitioner in clinical chemistry has an inappro- priate personal relationship with a commercial supplier o medical supplies and chemistry analyzers, there may be a potential issue with: a. publication development. b. con dentiality. c. selection o treatment. d. con ict o interest. 4. “Molecular testing” involves the clinical analysis o : a. atoms and molecules. b. nucleic acids. c. cellular components o blood. d. the physical structure o compounds. 5. Which one o the ollowing is not considered an ethical issue acing a clinical laboratorian? a. Allocation o resources b. Con icts o interest c. Discussion o one’ s salary d. Maintenance o con dentiality Re erences 1. Advanced Medical echnology Association (AdvaMed). Code o Ethics on interactions with health care pro essionals. Ef ective July 1, 2009. http://www.advamed.org/ (accessed on June 26, 2013). 2. Annesley M, Boyd JC, Ri ai N. Publication ethics: Clinical Chemistry editorial standards. Clin Chem 2009;55:1–4. 3. Council o Europe. Additional protocol to the convention or the protection o human rights and dignity o the human being with regard to the applica- tion o biology and medicine on biomedical research. Law Hum Genome Rev 2004;21:201–214. 4. European Diagnostic Manu acturers Association (EDMA). Part A: inter- action with health care pro essionals. http://www.edma-ivd.be/ (accessed June 26, 2013). 5. Gra C, Wager E, Bowman A, Fiack S, Scott-Lichter D, Robinson A. Best practice guidelines on publication ethics: a publisher’ s perspective. Int JClin Pract Suppl 2007;61:1–26. 6. Institute o Medicine. Con ict o interest in medical research, education, and practice. http://www.iom.edu (accessed June 26, 2013). 7. International Committee o Medical Journal Editors. Uni orm require- ments or manuscripts submitted to biomedical journals: writing and editing or biomedical publication. http://www.icmje.org/ (accessed June 26, 2013). 8. Malone B. Ethics code changes or diagnostics manu acturers. Clin Lab News 2009;35(6).
  • 32. 6 C H A P TE R Selection and Analytical Evaluation of Methods—With Statistical Techniques* *T e authors grate ully acknowledge the original contributions by T eodore Peters, Robert O. Kringle, and David D. Koch on which portions o this chapter are based. 2 Kristian Linnet, M.D., D.M.Sc., and James C. Boyd, M.D. Ob je c tive s 1. De ne the ollowing: A nalytical measurement range Median Bias Population Clinical sensitivity Precision Clinical speci city Random error Coe cient o variation Random sample Correlation coe cient Regression analysis Di erence plot Sample Error model Standard deviation Frequencydistribution Systematic error Gaussian probabilitydistribution Student t distribution Limit o detection T rueness Linearity U ncertainty Mean 2. List and describe three criteria that must be considerations in laboratorymethod selection, including the speci c parameters involved in each criterion. 3. Compare population and sample mean, population parameter and sample statistic, and population standard deviation and sample standard deviation, including a description o each, symbols used to express these, how they are calculated, and the in ormation theyprovide. 4. State the connection o the ollowing concepts to analytical methods: A ccuracy Linearity A nalytical sensitivity Precision A nalytical speci city Repeatability Calibration Reproducibility Limit o detection 5. List two common approaches used to objectively analyze data in a methods comparison study. 6. Describe the components o a di erence plot, including the plot’s use inmethodcomparisonandhowthe plotis interpreted. 7. Discuss assessment o error in an objective analysis o data in method comparison, including how error occurrence relates to anassay’s per ormance characteristics,the di erence between random and systematic error, what causes error, and howerror is evaluated in a di erence plot. 8. For the ollowing types o analyses, list the components o the analysis, its application in method comparison, how it is computed, how outliers a ect it, and how the results are interpreted: Deming regression Ordinaryleast-squares regression Nonparametric regression Regression 9. Describe the calibration hierarchy, including the tracing o val- ues o routine clinical chemistry measurements to a primary re erence, how the values are obtained, and the methods involved; draw a calibration hierarchygiven a speci c analyte. 10. Discuss the concept o uncertaintyin relation to clinicallabora- tory results, including the components o the standard uncer- tainty ormula and two ways in which uncertaintyis assessed. 11. Given appropriate values, state the ormula and calculate the ollowing: Coe cient o variation Population mean Coe cient o variation percent Precision analyses Deming regression Standard deviation Linear regression Standard uncertainty Ke y Wo rd s a n d De fin itio n s Analyte The substance being analyzed in an analytical procedure. Analyticalsensitivity The abilityo ananalyticalmethodtoassess small variations in the concentration o analyte. Analytical specif city The ability o an assay procedure to deter- mine speci cally the concentration o the target analyte in the presence o potentially inter ering substances or actors in the sample matrix. Bias In an analytical method, the di erence between the average value and the true value that is expressed numerically and is inverselyrelated to the trueness.
  • 33. CHAPTER 2 Selection and Analytical Evaluation of Methods—With Statistical Techniques 7 T e introduction o new or revised methods is a common task or laboratoriansworkingin theclinicallaboratory(Figure2-1). In practice, a new or revised method must be selected care ully and its per ormance evaluated thoroughly in the laboratory be ore it is adopted or routine use. T e establishment o a new method may also involve an evaluation o the eatures o the automated analyzer on which the method will be implemented. Method evaluation in the clinical laboratory is in uenced strongly by guidelines (e.g., see the Clinical and Laboratory Standard Institute [CLSI; www.clsi.org/; accessed July 6, 2013] and the International Organization or Standardization [ISO; www.iso.org/; accessed July 6, 2013]). In addition, meeting laboratory accreditation requirements has become an impor- tant aspect o the method selection and evaluation process. T is chapter presents an overview o considerations in the method selection process, ollowed by sections on basic sta- tistics, method evaluation, and method comparison. A list o abbreviations used in this chapter is provided in Box 2-1. Method Selection Optimal method selection involves consideration o (1) medical use ulness, (2) analytical per ormance, and (3) practical criteria. Medical Use ulness Criteria T e selection o appropriate methods or clinical laboratory assays is a vital part o rendering optimal patient care, and ad- vances in patient care are requently based on the use o new or improved laboratory tests. Ascertaining what is necessary clinically rom a laboratory test is the rst step in selecting a candidate method (see Fig- ure 2-1). Keyparameters, such as desired turnaround time and necessary clinical utility or an assay, o en are derived rom discussions between laboratorians and clinicians. When new diagnostic assays are introduced, reliable estimates o clini- cal sensitivity and speci city must be obtained by reviewing the literature or by conducting a clinical outcome study. With established analytes (the substances analyzed in an analytical procedure), a common scenario is the replacement o an older, labor-intensive method with a newer, automated assay that is more economical or daily use. Analytical Per ormance Criteria In evaluating the per ormance characteristics o a candidate method, (1) precision, (2) accuracy (trueness), (3) analytical range, (4) detection limit, and (5) analytical speci city are o prime importance. T e sections in this chapter on method Ke y Wo rd s a n d De fin itio n s —c o n t’d Calibration In relation to analytical methods, a unction that describes the relationship between instrument signal and con- centration o analyte. Commutability The equivalence o the mathematicalrelationships between the results o di erent measurement procedures or a re erence materialand or representative samples romhealthy and diseased individuals. Di erence plot Abias plot that shows the dispersion o observed di erences between the measurements o two methods as a unction o the average concentration o the measurements; also re erred to as a “Bland-A ltman plot.” Limit o detection A nassaycharacteristicde nedas thelowestvalue that signi cantlyexceeds the measurements o a blanksample. Matrix In relation to analytical methods, human serum that con- tains analytes. Measuring interval The analyte concentration range over which measurements are within the declared tolerances or impreci- sion and bias; also re erred to as “reportable range.” Method comparison Comparison o measurements bytwo meth- ods that is carried out objectively using statistical procedures and graphics displays. Ordinary least-squares regression (OLR) analysis A method used to estimate the unknown parameters in a linear regres- sion assessment per ormed to minimize the sum o squared vertical distances between observed responses and responses predicted bylinear approximation. Population In relation to analytical methods, the complete set o all observations that might occur as the result o per orming a particular procedure according to speci ed conditions. Random error Error that arises rom imprecision o measure- ment o the type that is described by a Gaussian distribution (e.g., caused bypipetting variability, signal variability). Re erence measurement procedure Aprocedure o highest ana- lytical quality that has been shown to yield values having an uncertainty o measurement commensurate with its intended use,especiallyin assessing the trueness o other measurement procedures or the same quantity and in characterizing re er- ence materials. Regression analysis Astatistical analysis that compares meas- urement relations between two analytical methods. Systematic error Error in measurement that arises rom calibra- tion bias or nonspeci city o an assay and, in the course o a number o analyses o the same analyte, remains constant (y-intercept deviation rom zero)or varies in a proportionalway (slope deviation romunity)based on the analyte concentration. T raceability In relation to analytical methods, a concept based on a chain o comparisons o measurements that lead to a known re erence value done toensure reasonable agreement between measurements o routine methods. T rueness Aqualitative termthat describes the closeness o agree- ment between the average value obtained rom a large series o results o measurements and a true value. Uncertainty Aparameterassociatedwiththeresulto ameasurement that characterizes the dispersion o the values that could reason- ablybe attributed tothe measure and, or, more briefy, uncertainty is a parameter characterizing the range o values within which the value o the quantitybeing measured is expected tolie.
  • 34. PART I Principles of Laboratory Medicine 8 evaluation and comparison contain outlines o these concepts and o their assessment. T e estimated per ormance param- eters or a method are related to quality goals that ensure ac- ceptable medical use o the test results (see section, “Analytical Goals”). From a practical point o view, the “ruggedness” o the method in routine use is o importance. When a new clinical analyzer is included in the overall evaluation process, various instrumental parameters also require evaluation, including (1) pipetting precision, (2) specimen-to-specimen carryover, (3) reagent-to-reagent car- ryover, (4) detector imprecision, (5) time to rst reportable result, (6) on-board reagent stability, (7) overall throughput, (8) mean time between instrument ailures,and (9) mean time to repair. In ormation on most o these parameters should be available rom the instrument manu acturer. Other (Practical) Criteria Various categories o candidate methods may be considered. New methods described in the scienti c literature may require “in-house” development. Commercial kit methods, on the other hand, are ready or implementation in the laboratory, o - ten in a “closed” analytical system on a dedicated instrument. When prospective methods are reviewed, attention should be given to the ollowing: 1. T e principle o the assay, with original re erences 2. T e detailed protocol or per orming the test 3. T e composition o reagents and re erence materials, the quantities provided, and their storage requirements (e.g., space, temperature, light, and humidity restrictions) applicable both be ore and a er the original containers are opened 4. T e stabilityo reagents and re erence materials (e.g., their shel li e) 5. echnologist time and required skills 6. Possible hazards and appropriate sa ety precautions according to relevant guidelines and legislation 7. T e type, quantity, and disposal o waste generated 8. Specimen requirements such as conditions or collec- tion, specimen volume requirements, the necessity or anticoagulants and preservatives, and necessary storage condition 9. T e re erence interval o the method, including in orma- tion on howit wasderived,typicalvaluesobtained in health and disease, and the necessity o determining a re erence interval or one’ s own institution (see Chapter 5 or details on how to generate a re erence interval) 10. Instrumental requirements and limitations 11. Cost-e ectiveness 12. Computer plat orms and inter acing to the laboratory in ormation system 13. T e availability o technical support, supplies, and service Other considerations should be taken into account. For example, is there suf cient space, electrical power, cooling, and plumbing or a newinstrument?Does the projected work- load match with the capacity o a new instrument? Is the test repertoire o a new instrument suf cient? What is the method o calibration, and what is its requency?Is staf ng o the labo- ratory suf cient or is training required? What are the appro- priate choices o quality control procedures and pro ciency testing? What is the estimated cost o per orming an assay using the proposed method, including the costs o calibrators, quality control specimens, and technologists’time? Basic Statistics In this section, undamental statistical concepts and techniques are introduced in the context o typical analytical investiga- tions. T e basic concepts o populations, samples, parameters, Quality control practices Routine analysis Implementation Method verification/ validation Method selection/ development Definition of quality goal Establish need Result report Figure 2-1 Flow diagram that illustrates the process o intro- ducing a new method into routine use. The diagram highlights the key steps o method selection, method evaluation, and qual- ity control. BOX 2-1 Abbreviations CI Con dence interval CV Coe cient o variation (=SD/x, where xis the concentration) CV % = CV100% CV A A nalyticalcoe cient o variation CV RB Randombias coe cient o variation ISO InternationalOrganization or Standardization OLR Ordinaryleast-squares regression analysis SD Standard deviation SEM Standard error o the mean = SD⁄√ N) SDA A nalyticalstandard deviation SDRB Randombias standard deviation xm M ean
  • 35. CHAPTER 2 Selection and Analytical Evaluation of Methods—With Statistical Techniques 9 statistics, and probability distributions are de ned and illus- trated. wo important probability distributions, Gaussian and Student t, are introduced and discussed. Frequency Dis tribution A graphical device or displaying a large set o data is the re- quency distribution, also called a histogram. Figure 2-2 shows a requency distribution displaying the results o serum γ-glutamyltrans erase (GG ) measurements o 100 apparently healthy 20- to 29-year-old men. T e requency distribution is constructed by dividing the measurement scale into cells o equal width, counting the number, ni, o values that all within each cell, and drawing a rectangle above each cell whose area (and height, because all cell widths are equal) is proportional to ni. In this example, the selected cells were 5 to 9, 10 to 14, 15 to 19, 20 to 24, 25 to 29, and so on, with 60 to 64 being the last cell. T e ordinate axis o the requency distribution gives the number o values alling within each cell. When this number is divided by the total number o values in the data set, the rela- tive requency in each cell is obtained. O en, the position o a subject’ s value within a distribu- tion o values is use ul medically. T e nonparametricapproach is used to determine directly the percentile o a given subject. When N subjects have been ranked according to their values, the n-percentile, Percn, may be estimated as the value o the (N[n/100] + 0.5) ordered observation. In cases o a noninteger value, interpolation is carried out between neighboring values. Population and Sample T e purpose o analytical work is to obtain in ormation and draw conclusions about characteristics o one or more popu- lations o values. In the GG example, the interest involves the location and spread o the population o GG values or 20- to 29-year-old healthy men. T us a working de nition o a population is the complete set o all observations that might occur as a result o per orming a particular procedure accord- ing to speci ed conditions. Most populations o interest in clinical chemistry are in - nite in size and so are impossible to study in their entirety. Usually a subgroup o observations is taken rom the popula- tion as a basis on which conclusions can be ormed about the population characteristics. T e group o observations that has actually been selected rom the population is called a sample. For example, the 100 GG values represent a sample rom a respective population. However, a sample is used to study the characteristics o a population only i it has been properly selected. For instance, i the analyst is interested in the popu- lation o GG values over various lots o materials and some time period, the sample must be selected to be representative o these actors as well as o the age, sex, and health actors. Consequently, exact speci cation o the population(s) o inter- est is necessary be ore a plan can be designed or obtaining the sample(s). Probability and Probability Distributions Consider again the requency distribution in Figure 2-2. In addition to the general location and spread o the GG determinations, other use ul in ormation is easily extracted rom this requency distribution. For instance, 96% (96 o 100) o the determinations are less than 55 U/L, and 91%(91 o 100) are greater than or equal to 10 but less than 50 U/L. Because the cell interval is 5 U/Lin this example, statements like these can be made only to the nearest 5 U/L. A larger sample would allow a smaller cell interval and more re ned statements. For a suf ciently large sample, the cell interval is made so small that the requency distribution is approx- imated by a continuous, smooth curve like that shown in Figure 2-3. In act, i the sample is large enough, we can consider this a close representation o the true population requency distribution. In general, the unctional orm o the population requency distribution curve o a variable x is denoted by (x). T e population requency distribution allows us to make probability statements about the GG o a randomly selected member o the population o healthy 20- to 29-year-old men. For example, the probability Pr(x > xa) that the GG value x o a randomly selected 20- to 29-year-old healthy man is greater than some particular value xa is equal to the area under the population requency distribution to the right o xa. I xa = 58, then rom Figure 2-3, Pr(x > 58) = 0.05. Similarly, the prob- ability Pr(xa < x < xb) that x is greater than xa but less than xb is equal to the area under the population requency distribution between xa and xb. For example, i xa = 9 and xb = 58, then rom Figure 2-3, Pr(9 < x < 58) = 0.90. Because the popula- tion requency distribution provides all in ormation about the probabilities o a randomly selected member o the popula- tion, it is called the probability distribution o the population. Although the true probability distribution is never exactly 5 0.05 10 0.90 0.05 15 20 25 30 35 40 GGT (U/L) 45 50 55 60 65 x 0.1 0.2 0.3 R e l a t i v e f r e q u e n c y f ( x) Figure 2-3 Population requency distribution o γ-GGT values. 5 10 15 20 GGT (U/L) 25 30 35 40 45 50 55 60 65 10 3 10 17 29 14 8 5 5 3 2 3 1 0 0.10 R e l a t i v e f r e q u e n c y n i / Σ n i F r e q u e n c y n i 0.20 0.30 20 30 Figure 2-2 Frequency distribution o 100 γ-GGT values.
  • 36. PART I Principles of Laboratory Medicine 10 known in practice, it is approximated with a large sample o observations. Parameters : Descriptive Meas ures o a Population Any population o values can be described by measures o its characteristics. A parameter is a constant that describes some particular characteristic o a population. Although most pop- ulations o interest in analytical work are in nite in size, or the ollowing de nitions we shall consider the population to be o nite size N, where N is very large. One important characteristic o a population is its central location. T e parameter most commonly used to describe the central location o a population o N values is the population mean (µ): µ= xi N An alternative parameter that indicates the central ten- dency o a population is the median, which is de ned as the 50th percentile, Perc50. Another important characteristic o a population is the dispersion o values about the population mean. A parameter very use ul in describing this dispersion o a population o N values is the population variance σ2 (sigma squared): (xi − µ)2 N 2 = T e population standard deviation σ, the positive square root o the population variance, is a parameter requently used to describe the population dispersion in the same units (e.g., mg/dL) as the population values. Statistics: Des criptive Measures o the Sample As was noted earlier, the clinical laboratorian usually has available only a ew observations rom the population o in- terest. A statisticis a value calculated rom the observations in a sample to describe a particular characteristic o that sample. T e sample mean xm is the arithmetic average o a sample, which is an estimate o µ. Likewise, the sample standard devi- ation (SD) is an estimate o σ, and the coef cient o variation (CV) is the ratio o the SD to the mean multiplied by 100%. T e equations used to calculate xm, SD, and CV, respectively, are as ollows: xm = xi N SD= (xi − xm)2 N− 1 = xi 2 − ( xi)2 N N− 1 CV= SD xm × 100% where xi is an individual measurement, and N is the number o sample measurements. Random Sampling A random selection rom a population is one in which each member o the population has an equal chance o being se- lected. A random sample is one in which each member o the sample is considered to be a random selection rom the popu- lation o interest. Although much o statistical analysis and in- terpretation depends on the assumption o a random sample rom some xed population, actual data collection o en does not satis y this assumption. In particular, or sequentially gen- erated data, it is o en true that observations adjacent to each other tend to be more alike than observations separated in time. A sample o such observations cannot be considered a sample o random selections rom a xed population. Fortu- nately, precautions can usually be taken in the design o an investigation to validate approximately the random sampling assumption. The Gauss ian Probability Distribution T e Gaussian probability distribution, which is illustrated in Figure 2-4, is o undamental importance in statistics or sev- eral reasons. As was mentioned earlier, a particular analytical value x will not usually be equal to the true value µ o the speci- men being measured. Rather, associated with this particular value x will be a particular measurement error, ε = x − µ, which is the result o many contributing sources o error. T ese mea- surement errors tend to ollow a probability distribution like that shown in Figure 2-4, where the errors are symmetrically distributed, with smaller errors occurringmore requentlythan larger ones, and with an expected value o 0. T is important act is known as the central limit e ect or distribution o er- rors: I a measurement error ε is the sum o many independent sources o error (ε1, ε2, …, εk), several o which are major con- tributors, the probabilitydistribution o the measurement error ε will tend to be Gaussian as the number o sources o error becomes large. Another reason or the importance o the Gaussian prob- ability distribution is that many statistical procedures are based on the assumption o a Gaussian distribution o values; this approach is commonly re erred to as parametric. Further- more, these procedures usually are not seriously invalidated by departures rom this assumption. Finally, the magnitude − − − Figure 2-4 The Gaussian probability distribution.