Pediatric Reference Intervals [8 ed.] 0128179392, 9780128179390

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Pediatric Reference Intervals Eight Edition Edward C.C. Wong, MD, FCAP Carlo Brugnara, MD Joely A. Straseski, PhD, DABCC Mark D. Kellogg, PhD, MT(ASCP), DABCC Khosrow Adeli, PhD, FCACB, DABCC

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the Publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This 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 field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher, nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. About AACC Dedicated to achieving better health through laboratory medicine, AACC brings together more than 50,000 clinical laboratory professionals, physicians, research scientists, and business leaders from around the world focused on clinical chemistry, molecular diagnostics, mass spectrometry, translational medicine, lab management, and other areas of progressing laboratory science. Since 1948, AACC has worked to advance the common interests of the field, providing programs that advance scientific collaboration, knowledge, expertise, and innovation. For more information, visit www.aacc.org. Published in cooperation with AACC Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-817939-0 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Stacy Masucci Acquisitions Editor: Ana Claudia Abad Garcia Editorial Project Manager: Mona Zahir Production Project Manager: Kiruthika Govindaraju Cover Designer: Christian J. Bilbow Typeset by TNQ Technologies

We dedicate this book to our children and grandchildren. We hope that children worldwide will benefit from this eighth edition of Pediatric Reference Intervals (formerly Pediatric Reference Ranges)

Foreword This invaluable volume on pediatric laboratory medicine is a very important contribution to patient care, now made even more useful by the addition of a greatly expanded chemistry section and more complete hematology and coagulation reference ranges. Every children’s hospital, pediatric department, and clinical laboratory should have this well-designed and easy-to-read manual close at hand. The editors are to be commended for their splendid addition to the quality of laboratory diagnosis. David G. Nathan, MD DanaeFarber Cancer Institute Boston, Massachusetts

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Preface The need for pediatric reference intervals is quite evident, as children and adolescents undergo a series of remarkable changes in growth, organ development, and sexual maturity from the time they are born to the time they become adults. For example, neonates and premature infants start off with immature hepatic, renal, and pulmonary function which can affect the way a wide variety of medications are metabolized. The rapid endocrine changes evident during puberty are a testament to the need for well-defined reference intervals in this age group. Thus, without appropriate reference intervals, laboratory testing becomes an inexact endeavor in futility.

How Do We Approach the Definition of Normal Reference Intervals? In the ideal situation, samples would be collected directly from a large number of healthy children of all age groups, the laboratory would test each sample, and those results would be used to determine statistically relevant reference intervals for the appropriate age partitions. However, we know this is not an easy task. Children are considered vulnerable subjects from a research perspective and, therefore, have limitations on the total volume of blood that can be safely collected from them. Strict protocols for consent/assent to participate in research studies may be challenging to administer to children and require parent or guardian involvement. Additionally, participants need to be carefully screened for disorders that might bias any measured results (1). The difficult nature of phlebotomy, particularly in younger children, can also cause emotional stress on parents who might not want their child to participate in a potentially painful procedure with no immediate benefit. Because of these and other practical challenges, it is often difficult to obtain adequate sample volumes from at least 120 healthy individuals to achieve a statistically accurate normative reference interval for an age partition. That challenge is compounded by the need for multiple age and sex partitions in growing and maturing children. Thus, relatively large studies with “healthy” volunteers are particularly difficult to perform but provide reassurance in the statistical determination of reference intervals that typically encompass the 2.5th to 97.5th percentiles of the reference population data (1).

Statistical Approaches Used to Determine Reference Intervals In lieu of the preferred approach of prospective collection of large sample numbers described above, several investigators have derived or used statistical methods on large databases of existing laboratory results to retrospectively determine appropriate reference intervals. One notable approach that has been included in previous editions of this book is the Hoffmann approximation (2). This approach typically uses either Chauvenet’s or Dixon’s criteria for removing outliers and involves plotting % cumulative frequency versus the laboratory

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value (or log of the value, if non-Gaussian distribution). Using this approach, one obtains a straight line typically within the central portion of the plotted curve. This straight line can be extrapolated to provide the 2.5th and 97.5th percentiles for the population being studied. An example for total iron-binding capacity is shown in Fig. 1(3). This approach is simplistic overall and has particular appeal in populations with limited data available from fresh sample collections from volunteers, such as pediatrics. Disadvantages include the need to be very selective in the population being considered since patients typically have testing performed due to a clinical concern and may not represent a “healthy” population. Other disadvantages include the need to carefully select appropriate age interval(s) and the need for a very large number of data points in order to perform these statistical calculations for reference interval derivation. There has been a recent validation of the Hoffmann approximation using a large database from a nationwide chain of clinical reference laboratories in the United States, without exclusions or filtering (4). A major criticism of the Hoffman approximation is the observation of narrower than expected reference intervals (5). There have, therefore, been a number of statistical approaches that have attempted to improve upon the Hoffman approximation. These include the Bhattacharya graphical method which involves the identification of Gaussian distributions within a distribution (6). Another is a computational (nongraphical) strategy using maximum likelihood through the expectationemaximization algorithm (7). As reviewed by Holmes and Buhr (5), however, all of these methods should be considered to be “indirect” estimates of reference intervals in healthy children and should be verified using data from such individuals. Another method that has recently been developed is the use of continuous pediatric reference curves for chemistry analytes (8). The advantages of this approach are that it provides a continuum of upper and lower reference intervals and avoids the use of reference

Figure 1 Hoffmann plot for total ironebinding capacity. Reprinted from Fig. 1 from Ref. (3) with permission from Elsevier.

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Figure 2 Example of continuous vs. Noncontinuous reference intervals and comparison of continuous versus partitioned reference intervals for BUN/creation ratios from ages 0 to 19 years. Reference values, continuous reference interval, and partitioned reference intervals are coded in either pink (females) or blue (males). Partitioned reference intervals for both sexes are in black. Shaded areas represent 95% confidence intervals. Reprinted from Fig. 1D (Ref. (9)) with permission from Elsevier.

intervals that are arbitrarily delineated which may lead to misclassification close to age “cutoff” points. Current laboratory information systems, however, will need future enhancements to incorporate these curves into routine laboratory reports (See Fig. 2) (9).

Method-Specific Differences Another potential complication to consider when determining pediatric reference intervals is technology. Given the plethora of assay methods and instruments available for purchase, it is extremely unlikely that every laboratory will use the same method or analyzer for measurement of a particular analyte. The crux of this concern is that the majority of analytes are not standardized among methods, resulting in values that cannot be compared well between laboratories. A good example is instrumentation that quantitates alkaline phosphatase levels. Recent proficiency testing data indicate mean values differed among commercial platforms by as much as 300%. Therefore, the method or commercial platform used to measure analytes used in pediatric reference interval determinations should be carefully considered and noted before interval use or adoption by a laboratory. It also speaks to the critical need for method-specific reference intervals.

Conclusion It is very clear that much work and thought goes into the development of pediatric reference intervals including careful consideration and screening of the population studied, the developmental status of the population, the instrumentation used, and the statistical

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methods employed. Future advances in laboratory information systems may allow for reporting of continuous pediatric reference intervals to better provide accurate reference intervals for patients. Reference intervals provide context to measured laboratory values and allow for the comparison between health and disease. Their importance, therefore, cannot be overstated.

References 1. Adeli K, Higgins V, Trajcevski K, White-Al Habeeb N. The Canadian laboratory initiative on pediatric reference intervals: a CALIPER white paper. Crit Rev Clin Lab Sci 2017;54:358e413. 2. Hoffmann RG. Statistics in the practice of medicine. JAMA 1963;185:864e873. 3. Soldin OP, Bierbower LH, Choi JJ, Choi JJ, Thompson-Hoffman S, Soldin SJ. Serum iron, ferritin, transferrin, total iron binding capacity, hs-CRP, LDL cholesterol and magnesium in children; new reference intervals using the Dade Dimension Clinical Chemistry System. Clin Chim Acta 2004;342: 211e217. 4. Katayev A, Balciza C, Seccombe DW. Establishing reference intervals for clinical laboratory test results: is there a better way? Am J Clin Pathol 2010;133:180e186. 5. Holmes DT, Buhr KA. Widespread Incorrect Implementation of the Hoffmann Method, the Correct Approach, and Modern Alternatives. Am J Clin Pathol 2019;151:328e336. 6. Bhattacharya C. A simple method of resolution of a distribution into Gaussian components. Biometrics 1967;23:115e135. 7. Redner RA, Walker HF. Mixture densities, maximum likelihood and the EM algorithm. SIAM Review 1984;26:195e239. 8. Hoq M, Matthews S, Karlaftis V, Burgess J, Cowley J, Donath S, Carlin J, Yen T, Ignjatovic V, Monagle P; HAPPI Kids Study Team. Reference values for 30 common biochemistry analytes across 5 different analyzers in neonates and children 30 days to 18 years of age. Clin Chem 2019;65:1317-1326. 9. Bohn MK, Higgins V, Adeli K. CALIPER paediatric reference intervals for the urea creatinine ratio in healthy children & adolescents. Clin Biochem 2020;76:31e34.

Introduction Welcome to the eighth edition of Pediatric Reference Intervals. This edition follows the publication of its predecessor in 2011, which was the last edition published by AACC Press. We are happy that this textbook has found its new home in Academic Press and the Elsevier family. The eighth edition witnessed a considerable refreshing of the editorial team with the addition of three new editors: Joely A. Straseski, Associate Professor (Clinical) in the Department of Pathology at the University of Utah School of Medicine, and Section Chief of Clinical Chemistry, Medical Director of Endocrine, and Codirector of Automated Core Laboratories at ARUP Laboratories. Dr. Straseski is the director of the CHILDx (Children’s Health Improvement through Laboratory Diagnostics) biorepository of samples from healthy children. Mark D. Kellogg, Director for Quality Programs and Associate Director of Chemistry in the Department of Laboratory Medicine at Boston Children’s Hospital and Assistant Professor of Pathology at Harvard Medical School. Khosrow Adeli, Head of Clinical Biochemistry at The Hospital for Sick Children and Professor at the Departments of Biochemistry, Physiology, and Laboratory Medicine and Pathobiology at the University of Toronto in Toronto, Canada. He is the principal investigator of the CALIPER (Canadian Laboratory Initiative on Pediatric Reference Intervals) project (www.caliperproject.org; www.caliperdatabase.org). This eighth edition of Pediatric Reference Intervals is a near-complete update of the analytes published in the prior edition. This new edition has been significantly strengthened in hematology with the inclusion of several new data sets and expanded in coagulation with the inclusion of several additional analytes. In choosing which publications and data to include in the book, we prioritized published studies that included normal pediatric populations and currently used instrumentation. Chemistry analytes have been expanded and reviewed for clinical relevance. A scoring/metric system was developed to evaluate the available literature based on the following criteria: age and type of publication, population size, whether ethnicity and method platform were reported, and availability/frequency of use of the method or platform. Scores were used to determine which publications to include when multiple were available. Where appropriate, the reader is directed to the original publication for details that exceed what is covered in this book. Similar to the seventh edition, we have kept the same user-friendly format with each analyte having the same layout. We hope this provides easy access to key information such as sample type, methodology used, source reference, patient population, and the statistical basis on which the reference intervals were derived.

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As a reminder to those that use reference intervals to evaluate clinical test results, reference intervals are meant as guidelines only and cannot be used to definitively diagnose a child’s disease state without correlating test results with the clinical condition. This is particularly important because values for both healthy and sick patients frequently overlap and interpretation within the context of the clinical situation is critical. We are indebted to the assistance provided by the residents, fellows, and trainees that have helped compile the literature and their critical analysis of the ranges provided: Grace Kroner, PhD (University of Utah), Shannon Steele (CALIPER, The Hospital for Sick Children), Mary Kathryn Bohn, PhD candidate (University of Toronto), Li Zha, PhD (Boston Children’s Hospital), and MAJ Angela Davis, PhD (Boston Children’s Hospital). This edition would not have been possible without their contributions. We would also like to thank our Elsevier Project Managers, Anna Dubnow and Mona Zahir for their assistance with this updated edition. We want to express our gratitude to Steven J. Soldin for having led the editorial team in the prior seven editions. We would also thank Ms. Lina Noh for her excellent administrative help in compiling and editing the hematology and coagulation sections. Edward C.C. Wong, MD, FCAP Carlo Brugnara, MD Joely A. Straseski, PhD, DABCC Mark D. Kellogg, PhD, MT(ASCP), DABCC Khosrow Adeli, PhD, FCACB, DABCC

1 Chemistry tests Acylcarnitine Profile Individual reference interval partitions not provided due to complexity. See Comment(s) section for details. Reference(s):

1. Teodoro-Morrison T, Kyriakopoulou L, Chen YK, et al. Dynamic biological changes in metabolic disease biomarkers in childhood and adolescence: A CALIPER study of healthy community children. Clinical Biochemistry 2015;48:828e36. DOI: 10.1016/j.clinbiochem.2015.05.005 2. Gucciardi A, Zaramella P, Costa I, M, et al. Analysis and interpretation of acylcarnitine profiles in dried blood spot and plasma of preterm and full-term newborns. Pediatric Research 2015;77:36e47. DOI: 10.1038/pr.2014.142

Specimen Type(s):

1. Serum. 2. Plasma.

Method(s):

1. LC-MS/MS. 2. UPLC-MS/MS.

Comment(s):

1. Full acylcarnitine reference intervals may be obtained from the CALIPER database (https://caliper. research.sickkids.ca/#/). Healthy volunteers from Toronto, Canada area. Reference intervals were calculated using nonparametric statistics for partitions of 120 or more samples. Otherwise, the robust statistical method (Horn and Pesce) was used. In both cases, 2.5th and 97.5th percentiles are provided. 2. See publication for reference intervals for each acylcarnitine species by gestational age. Neonates from Italy. See publication for exclusion criteria. Statistical method was not described.

Pediatric Reference Intervals. https://doi.org/10.1016/B978-0-12-817939-0.00001-3 Copyright © 2021 Elsevier Inc. All rights reserved.

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Adiponectin Female Source

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