By Editor on 5/30/2018
By Julie Shaw, Danijela Konforte, Gayle Waite, Michael Knauer and Paul Yip
Assays, especially those in clinical chemistry, are designed to measure analytes (i.e., the measurand) in the appropriate patient specimens. However, there is the potential for inaccurate analyte measurements when testing materials are different from patient specimens. Examples include quality control (QC) material, proficiency testing (PT) material, and other types of patient specimens such as body fluids.
Often these differences are attributed to matrix effects, where the matrix is defined as the totality of components of a material system except for the analyte. The matrix effect is an influence of a property of the sample, other than the measurand, on the measurement of the measurand according to a specified procedure and thereby on its measured value.1,2
In a perfect world, when these materials show analyte measurements equivalent to patient specimens, they are said to be commutable materials. Therefore, commutable PT specimens serve as true surrogates for clinical specimens and can be used to assess accuracy of a method.
However, materials used for QC and most PT programs are typically processed. As a result, the matrix is altered even if the original material is from a human source. When materials are non-commutable, a bias is usually observed across different methods that precludes the ability to draw conclusions about bias for actual patient samples.2,3 Most laboratory users recognize that inter-laboratory QC programs are limited to assessing bias within the same peer-group (e.g., reagent or manufacturer), which may shift when a new reagent lot is introduced although patient results remain the same. Table 1 outlines common factors that can lead to matrix effects.
Table 1: Sample Processing and Sample Handling Factors That Can Cause Matrix Effect
Distinct benefits of non-commutable versus commutable materials for PT surveys
In addition to the advantages of commutable materials stated above, this approach enables the accuracy-based assessment quantitative results in PT surveys. By having a reference laboratory assign a target value by a traceable method, a true assessment of bias can be made. Even in absence of a reference value, the relative bias to other field methods is an important aid in the comparability of results across different laboratories.
On the other hand, it is difficult to obtain native patient specimens that contain a wide range of analyte concentrations. Furthermore, producing large quantities of material is challenging without pooling of patient specimens to obtain sufficient volumes. There are also considerations related to storage and handling of PT materials. Preservatives may be required, and freezing materials ensure analyte stability. 2,3
Assessment of IQMH PT Surveys for Quantitative Analytes in Chemistry
The IQMH Chemistry Program4 employs four approaches for determining the assigned value for quantitative surveys:
When proficiency testing items are prepared by adding and mixing a certain amount of substances to a base material, assigned values can be obtained from calculation of masses or properties used.
2. Measurement by reference laboratory
The assigned values for some analytes are obtained from a single reference laboratory using recognized reference methods traceable to a national or international standard, for example HbA1c.
3. Consensus of participants’ results
The assigned value for many analytes is taken as the consensus of participant results. This is due to the lack of readily available or affordable reference values for medical analytes or parameters.
One of the following may be used:
For Quantitative Surveys:
- All-methods’ mean (AMM) – Mean of all participants regardless of method.
- Method-specific mean (MSM) – Mean of all participants using a specific instrument, principle and/or reagent. This is used when there are significant and consistent differences between methods.
The PT materials in the surveys for hemoglobin A1c (CHEM-HB) are completely unmodified. The material for oximetry (CHEM-OX), urine drug monitoring (DRUG-UR), DRUG (ethanol and tobramycin) and Immunology (IMGY) are minimally modified. The specimens in these surveys are considered commutable. Commutable material is frequently assessed using an AMM where possible. Using an AMM allows small groups of less than five participants to be formally graded in the PT program as a requirement for accreditation.
In contrast, materials in the surveys for routine chemistry (CHEM), urine chemistry (CHEM-UR), endocrinology (ENDO), hematology (HEMA), coagulation (COAG), red cell disorders (RCD), flow cytometry (FLOW), blood gases (CHEM-BG), oximetry (CHEM-OX) and point-of-care glucose (POCT-GL) are processed materials and considered non-commutable. Note that small peer groups with less than five participants cannot be assessed when a non-commutable material is used.
Is it appropriate to cite a matrix effect as a root or contributing cause in the investigation of discordant findings?
Matrix effect is one possible source of bias that can be a root or a contributing cause of a PT discordance. For detailed approaches used to investigate different sources of bias, please refer to the recent Elevate article: Bias in the Clinical Laboratory.5
Bias due to a matrix effect is usually identified by a process of elimination, i.e., when all other analytical sources of bias (technical, method, and instrument) are ruled out. If the PT survey materials are considered commutable, it is unlikely the bias is due to matrix effect unless supported by other data, usually through investigation by the participant laboratory. On the other hand, matrix effect is not a valid reason for surveys where analytes are assessed within the same manufacturer, principle, or reagent group.
Often method bias is confused for matrix effect. To differentiate, laboratories can refer to the cumulative PT reports provided by IQMH. Differences from the AMM but not the peer group mean would be expected with matrix effect, and appear randomly among different survey samples. Deviations from the peer group mean that consistently appear over-time would suggest bias not related to a matrix effect.
Finally, laboratories can also perform comparison studies between their method and another user in the same peer group as well as to an alternative method using patient specimens. This will help determine whether observed bias on PT surveys is with their instrument alone or whether their method has a bias against a comparable platform by a different vendor.
- Clinical and Laboratory Standards Institute. Performance: Evaluation of commutability of processed specimens. CLSI document EP14-A4, 2022.
- Miller WG, Jones GR, Horowitz GL, Weykamp C. Proficiency testing/external quality assessment: current challenges and future directions. Clin Chem. 2011 Dec;57(12):1670-80. doi: 10.1373/clinchem.2011.168641.
- Miller WG. Specimen materials, target values and commutability for external quality assessment (proficiency testing) schemes. Clin Chim Acta. 2003 Jan;327(1-2):25-37. doi: 10.1016/s0009-8981(02)00370-4.
- Institute for Quality Management in Health. IQMH Chemistry Program Information - Chemistry-General, Drug Monitoring, Endocrinology, Enzymes and Cardiac Markers, Immunology, Lipids, Point-of-Care Testing (Glucose Meters). [database on the Internet]. Toronto (ON): IQMH QView™. [Updated 2022-04-06; Published 2011-12-02; cited 2022-11-03]. Available from: https://qview.ca/QVIEW/FileView.aspx?resourceid=445574.
- Institute for Quality Management in Healthcare. Lianna Kyriakopoulou, Tracy Wade and Paul Yip, on behalf of the IQMH Chemistry Scientific Committee. Bias in the Clinical Laboratory. IQMH Elevate, January 2018. Available from: https://iqmh.org/Portals/1/Docs/Resources/News/Archive/2018/Elevate%202018-01.pdf.