Clinical & Laboratory Standards Institute: CLSI …Clinical and Laboratory Standards Institute Setting the standard for quality in clinical laboratory testing around the world. The

C57Mass Spectrometry for Androgen and Estrogen Measurements in Serum

This guideline is intended to aid the laboratorian in developing

appropriate procedures for the use of mass spectrometry in the

measurement of androgens and estrogens.

A guideline for global application developed through the Clinical and Laboratory Standards Institute consensus process.

1st Edition

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Clinical and Laboratory Standards Institute Setting the standard for quality in clinical laboratory testing around the world.

The Clinical and Laboratory Standards Institute (CLSI) is a not-for-profit membership organization that brings together the varied perspectives and expertise of the worldwide laboratory community for the advancement of a common cause: to foster excellence in laboratory medicine by developing and implementing clinical laboratory standards and guidelines that help laboratories fulfill their responsibilities with efficiency, effectiveness, and global applicability. Consensus Process

Consensus—the substantial agreement by materially affected, competent, and interested parties—is core to the development of all CLSI documents. It does not always connote unanimous agreement, but does mean that the participants in the development of a consensus document have considered and resolved all relevant objections and accept the resulting agreement. Commenting on Documents

CLSI documents undergo periodic evaluation and modification to keep pace with advancements in technologies, procedures, methods, and protocols affecting the laboratory or health care.

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Comments on published CLSI documents are equally essential, and may be submitted by anyone, at any time, on any document. All comments are addressed according to the consensus process by a committee of experts. Appeals Process

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C57, 1st ed. February 2015

Mass Spectrometry for Androgen and Estrogen Measurements in Serum Julianne Cook Botelho, PhD Lisa M. Sapp, MS, MBA Lorin M. Bachmann, PhD, DABCC Patrick M. Sluss, PhD, MA Zhimin Cao, MD, PhD, DABCC Samuel A. Testino, Jr., PhD Donald Walt Chandler, PhD Christina Wang, MD Nigel Clarke, PhD Randy A. Weintraub, MS, PhD Laurence M. Demers, PhD Regina G. Ziegler, PhD, MPH Robert L. Fitzgerald, PhD, DABCC Hubert W. Vesper, PhD M. P. George, MS

Abstract Clinical and Laboratory Standards Institute document C57—Mass Spectrometry for Androgen and Estrogen Measurements in Serum is intended to aid the laboratorian in developing appropriate procedures for the use of mass spectrometry (MS) in the measurement of androgens and estrogens. The primary objectives of this document are to provide guidance and establish uniform practices necessary for producing quality data for quantitation of androgens and estrogens. The guideline provides details specific to androgen and estrogen measurement procedures with respect to preexamination (preanalytical) considerations, MS technologies, measurement procedure and run validation, as well as postexamination (postanalytical) considerations. Clinical and Laboratory Standards Institute (CLSI). Mass Spectrometry for Androgen and Estrogen Measurements in Serum. 1st ed. CLSI guideline C57 (ISBN 1-56238-995-5 [Print]; ISBN 1-56238-996-3 [Electronic]). Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2015.

The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a document through two or more levels of review by the health care community, is an ongoing process. Users should expect revised editions of any given document. Because rapid changes in technology may affect the procedures, methods, and protocols in a standard or guideline, users should replace outdated editions with the current editions of CLSI documents. Current editions are listed in the CLSI catalog and posted on our website at www.clsi.org. If you or your organization is not a member and would like to become one, and to request a copy of the catalog, contact us at: Telephone: 610.688.0100; Fax: 610.688.0700; E-Mail: [email protected]; Website: www.clsi.org.

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C57, 1st ed.

ii

Copyright ©2015. Clinical and Laboratory Standards Institute. Except as stated below, any reproduction

of content from a CLSI copyrighted standard, guideline, companion product, or other material requires

express written consent from CLSI. All rights reserved. Interested parties may send permission requests to

[email protected].

CLSI hereby grants permission to each individual member or purchaser to make a single reproduction of

this publication for use in its laboratory procedure manual at a single site. To request permission to use

this publication in any other manner, e-mail [email protected].

Suggested Citation

CLSI. Mass Spectrometry for Androgen and Estrogen Measurements in Serum. 1st ed. CLSI guideline

C57. Wayne, PA: Clinical and Laboratory Standards Institute; 2015.

ISBN 1-56238-995-5 (Print)

ISBN 1-56238-996-3 (Electronic)

ISSN 1558-6502 (Print)

ISSN 2162-2914 (Electronic) Volume 35, Number 4

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mailto:[email protected]

mailto:[email protected]

C57, 1st ed.

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Contents

Abstract .................................................................................................................................................... i

Committee Membership ........................................................................................................................ iii

Foreword .............................................................................................................................................. vii

1 Scope .......................................................................................................................................... 1

2 Standard Precautions .................................................................................................................. 1

3 Terminology ............................................................................................................................... 2

3.1 A Note on Terminology ................................................................................................ 2 3.2 Definitions .................................................................................................................... 2 3.3 Abbreviations and Acronyms ....................................................................................... 4

4 Preexamination (Preanalytical) Considerations ......................................................................... 5

4.1 Specimen Requirements ............................................................................................... 5 4.2 Collection, Processing, and Storage .............................................................................. 5 4.3 Preparation of Assay Calibration Materials and Quality Control Samples................... 6 4.4 Sample Preparation and Derivatization ........................................................................ 8

5 Mass Spectrometry Technologies ............................................................................................ 13

5.1 Gas Chromatography Mass Spectrometry, Liquid Chromatography Mass

Spectrometry, Tandem Mass Spectrometry ................................................................ 13 5.2 Measurement Procedure Characteristics for Steroid Hormone Measurement

by Liquid Chromatography Tandem Mass Spectrometry ........................................... 18

6 Measurement Procedure Validation/Characterization – Analytical Parameters ...................... 21

6.1 Accuracy/Bias ............................................................................................................. 22 6.2 Specificity/Selectivity of the Process .......................................................................... 22 6.3 Carryover .................................................................................................................... 23 6.4 Imprecision ................................................................................................................. 23 6.5 Linearity ...................................................................................................................... 24 6.6 Sensitivity ................................................................................................................... 24 6.7 Measurement Uncertainty ........................................................................................... 24

7 Result Evaluation and Reporting ............................................................................................. 24

7.1 Assay Setup................................................................................................................. 24 7.2 Data Collection ........................................................................................................... 26 7.3 Use of Confirmation Ions ........................................................................................... 28 7.4 Quality Control Monitoring ........................................................................................ 28

8 Quality Assurance Procedures ................................................................................................. 29

8.1 Staff Training and Competency Assessment .............................................................. 29 8.2 Facility and Resource Management ............................................................................ 29 8.3 Policies and Procedures .............................................................................................. 30 8.4 Quality Assessment and Improvement ....................................................................... 30 8.5 Proficiency Testing ..................................................................................................... 31

9 Harmonization of Results ........................................................................................................ 31

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Contents (Continued)

10 Postexamination (Postanalytical) Considerations .................................................................... 33

10.1 Reference Intervals ..................................................................................................... 33 10.2 Data Evaluation and Reporting ................................................................................... 34

References ............................................................................................................................................. 35

Appendix A. Examples of Published Transitions for Selected Reaction Monitoring of

Nonderivatized Steroid Hormones by Liquid Chromatography Tandem Mass Spectrometry ............. 40

Appendix B. Androgens, Estrogens, and Analogs ................................................................................ 43

Appendix C. Checklist for Run Evaluation .......................................................................................... 45

Appendix D. Metrological Institutions ................................................................................................. 46

The Quality Management System Approach ........................................................................................ 48

Related CLSI Reference Materials ....................................................................................................... 50

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Foreword

Androgen and estrogen measurements are widely used in clinical research, public health assessments, and

patient care; however, problems that impede the translation of research and clinical findings into viable

information for clinicians and scientists have been reported in the performance of these tests. As proposed

by the Endocrine Society in a 2007 position statement1 on measuring testosterone and concluded from the

2008 Centers for Disease Control and Prevention workshop2 on steroid hormone testing, mass

spectrometric procedures can overcome some of the current limitations in testing.

Mass spectrometry (MS) assays need to be developed and properly validated by the laboratory. This new

technology, however, is not commonly used in the clinical laboratory and clinical chemists frequently are

not familiar with developing these kinds of measurement procedures. As a result, the purpose of this

document is to provide accurate, state-of-the-art information and guidance for the appropriate use of MS

in the clinical laboratory for selected androgen and estrogen measurements in serum. Thus, this guideline

may help in overcoming some of the current limitations in androgen and estrogen testing, and therefore

aid in improving patient care and research translation.

Key Words

Androgen, estrogen, mass spectrometry, selected reaction monitoring, steroids

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C57, 1st ed.

©Clinical and Laboratory Standards Institute. All rights reserved. 1

Mass Spectrometry for Androgen and Estrogen Measurements in Serum

1 Scope

This guideline describes principles, requirements, and recommendations of current mass spectrometry

(MS) measurement procedures for routine analysis of androgens and estrogens in serum. The main focus

of this document is on the analytical validation and clinical application of androgen and estrogen

measurement procedures using MS. It includes guidance, references, and QA parameters that will assist

with the implementation and operation of MS systems. Information on maintaining appropriate

instrument settings and performance parameters, approaches to ensure accurate and precise

measurements, measurement procedure validation requirements, QA procedures, and interpretation and

reporting of results are included. Recommendations are included for sample preparation, and pre- and

postexamination (pre- and postanalytical) considerations.

The intended users of this guideline are laboratorians who perform or plan to perform androgen and/or

estrogen tests by MS, MS assay developers, and physicians and researchers involved in androgen and/or

estrogen testing.

A general, comprehensive review of MS technologies in the clinical laboratory is provided in CLSI

document C50.3 This guideline is limited to the measurement of total androgens and/or estrogens in

serum, referring to the free, bioavailable, albumin-bound androgens and estrogens, and free, bioavailable,

sex hormone–binding globulin (SHBG)–bound androgens and estrogens. The focus of this guideline is

limited to the measurement of androgens and estrogens commonly used in clinical and research settings

that include, but are not limited to: dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate

(DHEAs), androstenedione, testosterone (T), dihydrotestosterone (DHT), estrone (E1), estrone sulfate

(E1s), estradiol (E2), and estriol (E3). This guideline provides information on MS that relates to testing of

the above-mentioned steroid hormones. In addition, the purpose of this document is to provide guidance

on the appropriate use of MS for androgen and estrogen measurements and cannot cover all the

possibilities in this rapidly developing field. The recommendations provided should be interpreted in light

of the continuing progression in this discipline.

2 Standard Precautions

Because it is often impossible to know what isolates or specimens might be infectious, all patient and

laboratory specimens are treated as infectious and handled according to “standard precautions.” Standard

precautions are guidelines that combine the major features of “universal precautions and body substance

isolation” practices. Standard precautions cover the transmission of all known infectious agents and thus

are more comprehensive than universal precautions, which are intended to apply only to transmission of

bloodborne pathogens. The Centers for Disease Control and Prevention address this topic in published

guidelines that focus on the daily operations of diagnostic medicine in human and animal medicine while

encouraging a culture of safety in the laboratory.4 For specific precautions for preventing the laboratory

transmission of all known infectious agents from laboratory instruments and materials, and for

recommendations for the management of exposure to all known infectious diseases, refer to CLSI

document M29.5

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C57, 1st ed.


3 Terminology

3.1 A Note on Terminology

CLSI, as a global leader in standardization, is firmly committed to achieving global harmonization

wherever possible. Harmonization is a process of recognizing, understanding, and explaining differences

while taking steps to achieve worldwide uniformity. CLSI recognizes that medical conventions in the

global metrological community have evolved differently in the United States, Europe, and elsewhere; that

these differences are reflected in CLSI, International Organization for Standardization (ISO), and

European Committee for Standardization (CEN) documents; and that legally required use of terms,

regional usage, and different consensus timelines are all important considerations in the harmonization

process. In light of this, CLSI’s consensus process for development and revision of standards and

guidelines focuses on harmonization of terms to facilitate the global application of standards and

guidelines.

3.2 Definitions

accuracy (measurement) – closeness of agreement between a measured quantity value and a true

quantity value of a measurand (JCGM 200:20126).

analyte – component represented in the name of a measurable quantity (ISO 175117); NOTE 1: In the

type of quantity “mass of protein in 24-hour urine,” “protein” is the analyte. In “amount of substance of

glucose in plasma,” “glucose” is the analyte. In both cases, the long phrase represents the measurand

(ISO 175117); NOTE 2: In the type of quantity “catalytic concentration of lactate dehydrogenase

isoenzyme 1 in plasma,” “lactate dehydrogenase isoenzyme 1” is the analyte (ISO 181538).

bias – the difference between the expectation of the test results and an accepted reference value (ISO

5725-19).

calibration – operation that, under specified conditions, in a first step, establishes a relation between the

quantity values with measurement uncertainties provided by measurement standards and corresponding

indications with associated measurement uncertainties and, in a second step, uses this information to

establish a relation for obtaining a measurement result from an indication (JCGM 200:20126); NOTE:

According to the US Code of Federal Regulations, calibration is the process of testing and adjusting an

instrument or test system to establish a correlation between the measurement response and the value of

the concentration or amount of the substance that is being measured by the test procedure (42 CFR

493.210).

error (measurement)//measurement error – measured quantity value minus a reference quantity value

(JCGM 200:20126).

imprecision – dispersion of independent results of measurements obtained under specified conditions;

NOTE: It is expressed numerically as standard deviation or coefficient of variation.

limit of quantitation (LoQ) – lowest amount of a measurand in a material that can be quantitatively

determined with stated accuracy (as total error or as independent requirements for bias and precision),

under stated experimental conditions (modified from ISO 18113-111).

lower limit of the measuring interval (LLMI) – the lowest measurand concentration at which all

defined performance characteristics of the measurement procedure are met; NOTE: Formerly, the term

“lower limit of quantitation” was used in CLSI documents.

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The Quality Management System Approach Clinical and Laboratory Standards Institute (CLSI) subscribes to a quality management system (QMS) approach in

the development of standards and guidelines, which facilitates project management; defines a document structure via

a template; and provides a process to identify needed documents. The QMS approach applies a core set of “quality

system essentials” (QSEs), basic to any organization, to all operations in any health care service’s path of workflow

(ie, operational aspects that define how a particular product or service is provided). The QSEs provide the

framework for delivery of any type of product or service, serving as a manager’s guide. The QSEs are as follows:

Organization Personnel Process Management Nonconforming Event Management

Customer Focus Purchasing and Inventory Documents and Records Assessments

Facilities and Safety Equipment Information Management Continual Improvement

C57 addresses the QSE indicated by an “X.” For a description of the other documents listed in the grid, please refer

to the Related CLSI Reference Materials section on page 50.

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Path of Workflow

A path of workflow is the description of the necessary processes to deliver the particular product or service that the

organization or entity provides. A laboratory path of workflow consists of the sequential processes: preexamination,

examination, and postexamination and their respective sequential subprocesses. All laboratories follow these

processes to deliver the laboratory’s services, namely quality laboratory information.

C57 addresses the clinical laboratory path of workflow process indicated by an “X.” For a description of the other

documents listed in the grid, please refer to the Related CLSI Reference Materials section on the following page.

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Related CLSI Reference Materials C50 Mass Spectrometry in the Clinical Laboratory: General Principles and Guidance. 1st ed., 2007. This

guideline provides a general understanding of mass spectrometry and the principles that dictate its application

in the clinical laboratory. It includes guidance, references, and quality assurance markers that will assist with

the implementation and correct operation of a mass spectrometry (MS) system for its many applications.

Information on maintaining optimum performance, approaches to ensuring accurate and precise mass

measurement, verification of methods, quality control of assays within and between instruments, instrument

troubleshooting, sample preparation, interpretation of results, and limitations of the technology is included. A

CLSI-IFCC joint project.

EP05 Evaluation of Precision of Quantitative Measurement Procedures. 3rd ed., 2014. This document provides

guidance for evaluating the precision performance of quantitative measurement procedures. It is intended for

manufacturers of quantitative measurement procedures and for laboratories that develop or modify such

procedures.

EP06 Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach. 1st ed.,

2003. This document provides guidance for characterizing the linearity of a method during a method

evaluation; for checking linearity as part of routine quality assurance; and for determining and stating a

manufacturer’s claim for linear range.

EP07 Interference Testing in Clinical Chemistry. 2nd ed., 2005. This document provides background

information, guidance, and experimental procedures for investigating, identifying, and characterizing the

effects of interfering substances on clinical chemistry test results.

EP09 Measurement Procedure Comparison and Bias Estimation Using Patient Samples. 3rd ed., 2013. This

document addresses the design of measurement procedure comparison experiments using patient samples and

subsequent data analysis techniques used to determine the bias between two in vitro diagnostic measurement

procedures.

EP10 Preliminary Evaluation of Quantitative Clinical Laboratory Measurement Procedures. 3rd ed., 2014.

This guideline provides experimental design and data analysis for preliminary evaluation of the performance

of a measurement procedure or device.

EP14 Evaluation of Commutability of Processed Samples. 3rd ed., 2014. This document provides guidance for

evaluating the commutability of processed samples by determining if they behave differently than unprocessed

patient samples when two quantitative measurement procedures are compared.

EP15 User Verification of Precision and Estimation of Bias. 3rd ed., 2014. This document describes the

estimation of imprecision and of bias for clinical laboratory quantitative measurement procedures using a

protocol that can be completed within as few as five days.

EP17 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures. 2nd ed., 2012. This document provides guidance for evaluation and documentation of the detection capabilities of clinical

laboratory measurement procedures (ie, limits of blank, detection and quantitation), for verification of

manufacturers’ detection capability claims, and for the proper use and interpretation of different detection

capability estimates.

EP23™ Laboratory Quality Control Based on Risk Management. 1st ed., 2011. This document provides guidance

based on risk management for laboratories to develop quality control plans tailored to the particular

combination of measuring system, laboratory setting, and clinical application of the test.

EP28 Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory. 3rd ed., 2010. This

document contains guidelines for determining reference values and reference intervals for quantitative clinical

laboratory tests. A CLSI-IFCC joint project.

CLSI documents are continually reviewed and revised through the CLSI consensus process; therefore, readers should refer to

the most current editions.

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Related CLSI Reference Materials (Continued) EP30 Characterization and Qualification of Commutable Reference Materials for Laboratory Medicine. 1st

ed., 2010. This document provides information to help material manufacturers in the production and

characterization of commutable reference materials, as well as assist assay manufacturers and laboratorians in

the appropriate use of these materials for calibration and trueness assessment of in vitro diagnostic medical

devices.

EP32

Metrological Traceability and Its Implementation. 1st ed., 2006. This document provides guidance to

manufacturers for establishing and reporting metrological traceability.

GP44 Procedures for the Handling and Processing of Blood Specimens for Common Laboratory Tests. 4th

ed., 2010. This document includes criteria for preparing an optimal serum or plasma sample and for the

devices used to process blood specimens.

M29 Protection of Laboratory Workers From Occupationally Acquired Infections. 4th ed., 2014. Based on

US regulations, this document provides guidance on the risk of transmission of infectious agents by aerosols,

droplets, blood, and body substances in a laboratory setting; specific precautions for preventing the laboratory

transmission of microbial infection from laboratory instruments and materials; and recommendations for the

management of exposure to infectious agents.

QMS01 Quality Management System: A Model for Laboratory Services. 4th ed., 2011. This document provides a

model for medical laboratories that will assist with implementation and maintenance of an effective quality

management system.

QMS06 Quality Management System: Continual Improvement. 3rd ed., 2011. This guideline considers continual

improvement as an ongoing, systematic effort that is an essential component of a quality management system.

A continual improvement program may consist of fundamental processes and common supporting elements

described in this guideline.

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