What is standardization and a standardized test?
Standardization performed by CDC is an activity in which the analytical accuracy, precision, and other analytical performance parameters of a laboratory test are assessed against established, clinically relevant analytical performance goals. The accuracy, whenever possible, is assessed by comparing a test measurement against results obtained with a metrological reference method. Thus, a standardized laboratory test is a test that has demonstrated, through an assessment by CDC, an analytical performance (such as accuracy and precision), which consistently met specific analytical performance goals.
How can laboratories collaborate with CDC to assess the analytical accuracy and precision of their diagnostic tests?
Manufacturers of diagnostic products and lab-developed tests can enroll in Phase 1 and/or Phase 2 of the CDC Hormone Standardization-Certification Program (HoSt) to assess accuracy and precision of their tests. Phase 1 is the assessment phase and Phase 2 is the verification/certification phase.
In Phase 1, laboratories are given a 40-sample panel (typically) of single-donor sera including reference values. These samples are used to perform a bias assessment and to adjust calibration, as needed, prior to the start of Phase 2.
Participation in Phase 1 is optional. During this phase, more than 40 single-donor samples, up to 120, can be provided for additional assessments. Additional Phase 1 samples can also be requested at any time during Phase 2 enrollment to further investigate potential issues with assays.
Phase 2 consists of four blinded, quarterly challenges that include 10 single-donor samples each. Phase 2 occurs over the course of 1 year. Results from each blinded challenge are used to perform bias and imprecision assessments of the method. Certification is provided to assays that meet performance criteria.
How do laboratories obtain CDC certification?
Certification can be obtained only by enrolling in HoSt-Phase 2. Manufacturers of diagnostic products and lab-developed tests receive four blinded quarterly challenges that include 10 single-donor samples each, over the course of a year. Results from each blinded challenge are used to perform bias and imprecision assessments of each assay. Certifications are issued to assays that meet performance criteria. Certification is valid for one quarter. Certified laboratories will be added, with permission, to CDC’s estradiol or testosterone certified laboratories list.
How can laboratories collaborate with CDC to monitor the accuracy of their studies and clinical trials?
Principal investigators and researchers interested in monitoring the accuracy of their research studies and clinical trials can contact CDC (Standardization@cdc.gov) to discuss how blinded, accuracy-based, quality control samples can benefit their studies. Laboratories interested in a program to monitor the accuracy of their method can contact CDC about the Accuracy-based Monitoring Program (AMP).
What do CDC’s steroid hormone reference methods measure?
CDC’s steroid hormone reference methods provide highly accurate measurements of total testosterone1 and estradiol2. The Joint Committee for Traceability in Laboratory Medicine (JCTLM) database lists these methods as higher-order reference measurement procedures. As such, they can be used to determine the accuracy of commercial assays and laboratory-developed tests. The steroid hormone reference methods are comparable to other reference methods, such as those used by the National Institute for Standards and Technology and the University of Ghent.
What is traceability in laboratory medicine?
Traceability in laboratory medicine describes a process used to link a patient’s results to a higher-order reference material or reference method. The primary reference material used to calibrate the higher-order reference method for testosterone is A-NMI M914b, and NMIJ CRM 6004-a is used for estradiol.
The higher-order reference method assigns reference values to serum samples. These serum samples are then used to calibrate a routine steroid hormone test that measures patient samples. In this process, measurement results for patient samples are traceable back to A-NMI M914b for testosterone, and NMIJ CRM 6004-a for estradiol.
Establishing traceability in laboratory medicine is important because it defines the point of reference to which patient measurements are linked. This helps to ensure comparable measurements in patient care.
Traceability in laboratory medicine describes a process used to link a patient’s results to a reference material or reference method. For vitamin D, SRM 2972a is used to calibrate a reference method. The reference method assigns reference values to serum samples. These serum samples are then used to calibrate a routine vitamin D test used to measure patient samples. In this process, measurement results for patient samples are traceable to SRM 2972a.
Establishing traceability in laboratory medicine is important because it defines the point of reference to which patient measurements are linked. This helps to ensure measurements in patient care are comparable.
What is the Joint Committee for Traceability in Laboratory Medicine (JCTLM)?
The Joint Committee on Traceability in Laboratory Medicine (JCTLM) was created in 2002 through a declaration of cooperation between the International Bureau of Weights and Measures, the International Federation for Clinical Chemistry and Laboratory Medicine, and the International Laboratory Accreditation Cooperation. One of its main objectives is to promote traceability to appropriate measurement standards in International Organization for Standardization (ISO) documents 17511, 17025, and 18153. JCTLM maintains a database with reference methods that meet the criteria mentioned in these ISO standards.
What does it mean to be certified?
Participants that are certified have analyzed HoSt samples for four consecutive quarters (40 samples), and their data have met certification criteria after evaluation based on CLSI EP9.
What are the criteria?
Current CDC-HoSt Performance Criteria for Certification
|Estradiol*||±12.5% bias if >20 pg/mL,
±2.5 pg/mL bias if ≤20 pg/mL,
* Criteria included in performance report but not currently used for certification
** 80% of reported samples must meet bias criteria for Estradiol certification
What information is included in the list of certified participants?
The lists of estradiol and testosterone certified participants includes the following information: date certified, name/type of assay, reportable range, proportion of individual samples meeting criteria, contact details, and the date of certification. Proportion of samples meeting bias criteria is listed to help end-users make knowledgeable decisions regarding which assay or laboratory to use for testing purposes.
What is the difference between mean bias and sample bias?
Mean bias is the average bias of all samples used in the certification phase (generally 40 samples). This mean bias is used as one of the certification criteria. The sample bias is the bias of an individual sample compared to the reference value. The percentage of individual samples meeting analytical performance criteria for bias can be found on the lists of estradiol and testosterone certified participants. CDC started listing this information in 2017.
What does it mean when participants are no longer included on the list of certified participants?
HoSt Certification is active for one year. Participants are removed from the list 6 months after certification becomes inactive.
How long does it take until participants are listed?
The list is updated quarterly. Once participants have completed four consecutive quarters, their results will be evaluated and those participants meeting certification criteria are listed the next quarter.
What is the goal of HoSt certification?
The goal of certification through HoSt is to ensure that tests for steroid hormones, such as total testosterone and estradiol, produce accurate results. This is achieved by standardizing commercial tests at the manufacturer level. In this way, laboratories know the commercial tests and testing instrument they buy are standardized. CDC’s program also offers certification for laboratories that use laboratory-developed tests, and tests by uncertified manufacturers.
What makes HoSt unique?
CDC’s HoSt is unique because it uses unmodified, high-quality serum samples for evaluating analytical bias and precision. This allows analytical performance assessment with sera similar to those used in patient care settings. The use of this type of sera is required because modified sera, such as those that are pooled or otherwise modified, can introduce so-called “matrix effects,” which can produce incorrect measurement results and conclusions about the accuracy of a test, though the test would be considered accurate when using patient samples.
Why is the certification process important?
The certification process ensures that the method in question is accurate over time. Many clinical laboratories rely on test manufacturers to maintain certified methods.
What is involved in the certification process?
A manufacturer or clinical laboratory that wants to be involved in the certification process should contact CDC’s HoSt Program and obtain the testosterone and estradiol protocols.
Can more than one test be certified with the same set of samples?
To be certified, each test must be enrolled separately and receive its own set of samples.
How long will the certification process take from sending samples to receiving certification?
The time needed to complete the certification process depends on several factors:
- How long it takes participants to receive their samples
- How long it takes to complete the analytical runs
- How long it takes to meet analytical performance criteria for four consecutive quarters
Given the variables involved, the entire process would take 1 year in the best-case scenario.
Does HoSt have a protocol for recertification?
Yes. Participants are encouraged to re-enroll in the program upon receiving certification to prevent gaps in certification status. See for further information.
What is the best way to verify that my analytical system has low bias before embarking on a full certification effort?
The best way to verify low bias in an assessment is to perform a comparison with the Hormone Reference Laboratory using the 40 patient samples provided in Phase 1 of the program. Phase 1 can be used to assess bias and recalibrate methods as necessary before beginning Phase 2.
See estradiol and testosterone program protocols for more details about Phase 1 and Phase 2.
Should my laboratory send in standards or calibrators to be analyzed by the reference method first?
Reference measurement services are offered through HoSt, but sending standards to be analyzed by the reference method before enrolling it is not necessary. For more information on reference measurement services, contact Standardization@cdc.gov.
Can CDC’s HoSt assign values to samples provided by my laboratory?
CDC works on meeting these requests, but such services are subject to availability of resources. For more information on reference measurement services, contact Standardization@cdc.gov.
If my laboratory has “out-of-control” runs during analysis of certification samples, or if the samples analyzed include “out-of-control” values, can I choose not to report the unusual values?
Laboratories should apply their rules and policies for reporting results. If you have “out-of-control” runs during the certification process, you should investigate the reasons for these deviations before you re-analyze certification samples.
What materials are used in the CDC standardization programs?
Reference materials used in the programs are prepared from unaltered single-donor human serum, in accordance with CLSI guideline C37-A (Preparation and validation of commutable frozen human serum pools as secondary reference materials for cholesterol measurement procedures; approved guideline).
The HoSt Program reference materials are stored and maintained frozen, at or below -70°C. All such materials are shipped to domestic participating laboratories by air mail. Samples are shipped in special insulated containers with sufficient dry ice to last at least 48 hours. Additional dry ice is added, as permitted, for delivery to international participants. Shipments of samples to regions that do not accept dry ice can be arranged. On arrival, the frozen reference material must be immediately transferred to a freezer for storage at -70°C.
Is there a yearly deadline for enrollment?
Participants may enroll in the program at any time, and may begin receiving samples during any of the 4 quarterly shipments (February, May, August, and November).