Clinical Laboratory Testing Interference


Interference in clinical laboratory testing can create discrepancies in test results which can lead to patient harm. In clinical chemistry, interference is defined as a cause of medically significant difference in the measurand test result due to another component or property of the sample. Although performance is monitored by internal QC and external quality assessment procedures, laboratories can’t easily detect error caused by interferents.

The three main contributors to testing inaccuracy are imprecision, method-specific difference, and specimen-specific difference (interference).1,2 Frequently, measurement procedure evaluations estimate only the first two. Specimen-specific difference, or interference, is often viewed as an isolated occurrence rather than as a quantifiable characteristic of the measurement procedure.

Interferents may originate from endogenous and exogenous sources:

  • Metabolites produced in pathological conditions such as diabetes mellitus
  • Compounds introduced during patient treatment like drugs, plasma expanders, and anticoagulants
  • Substances ingested by the patient like alcohol or nutritional supplements
  • Substances added during specimen preparation such as anticoagulants, preservatives, and stabilizers
  • Contaminants inadvertently introduced during specimen handling like hand cream or powder from gloves
  • The specimen matrix itself (ie, chemical or physical properties that differ from the native specimen [eg, crenated red blood cells])

Interference is identified by screening for an interference effect followed by quantifying interference effects. This is accomplished by using a paired-difference study, when warranted. In a paired-difference study, the prepared sample contains the potential interferent, and the prepared control sample does not. All other potentially contributing factors remain the same in the test and control samples. Interference is calculated as the difference between the prepared test and control samples.

Interference can occur before testing during the preexamination (pre-analytical) phase or during the examination (analytical) phase.

A change in the measurand or its concentration before analysis is commonly termed a “preexamination effect.” Although such effects may influence the medical use of a laboratory result, they are not analytical interference.

Common examples of preexamination effects are:

  • In vivo (physiological) drug effects, such as a change in circulating hormone concentration in response to a drug
  • Chemical alteration of the measurand (eg, by hydrolysis, oxidation, photodecomposition)
  • Physical alteration of the measurand, such as enzyme denaturation due to extreme temperature exposure
  • Evaporation or dilution of the specimen
  • Contamination with additional measurands (eg, from intravenous infusion)
  • Loss of a substance from prolonged contact with blood cells (ie, red and white blood cells or platelets consuming glucose)
  • Analytes that are released from blood cells (eg, platelet granula content)

Some causes of examination (analytical) interference are as follows:

  • Chemical artifacts: The interferent may suppress the reaction by competing for reagents, inhibiting indicator reactions, or altering the form of the measurand through complexation or precipitation.
  • Detection artifacts: The interferent might have properties similar to the measurand that are detected and measured.
  • Physical artifacts: The interferent might alter a physical property of the specimen matrix (eg, viscosity), causing an apparent change in the concentration of the measurand.
  • Enzyme inhibition: The interferent might alter the activity of an enzyme (measurand or reagent) by sequestering metal activators, binding to the catalytic site, or oxidizing essential sulfhydryl groups.
  • Nonselectivity: The interferent might react in the same manner as the measurand.
  • Additive artifact: An interferent or additional measurand might come from cells (eg, potassium release from cell lysis) or from intravenous fluids.

CLSI’s Interference Testing in Clinical Chemistry—EP07, provides background information, guidance, and experimental procedures for investigating, identifying, and characterizing the effects of interferents on clinical chemistry test results. EP07 assists manufacturers and laboratories with evaluating interferents, determining the extent of interfering effects in the context of medical needs, and informing customers of known sources of medically significant error. EP07 identifies many potential interferents to be evaluated in the risk management process.3 Laboratory scientists and manufacturers need to understand the scientific concepts, make informed choices, and work together toward the common goal of safeguarding patient care. Identifying an interference effect, evaluating its medical significance, determining its underlying cause, and ultimately improving the measurement procedure necessitates close cooperation between the laboratory and the manufacturer.

CLSI also offers a solution package of seven documents that focuses on topics such as interference, linearity, reference intervals, trueness, and precision, including related troubleshooting. Topics covered in this package correspond to CLSI quality system essential Process Management and ISO 15189 sections 5.4 Pre-examination processes and 5.6 Ensuring quality of examination results.


  1. Krouwer JS. How to improve total error modeling by accounting for error sources beyond imprecision and bias. Clin Chem. 2001;47(7):1329-1331.
  2. Krouwer JS. The danger of using total error models to compare glucose meter performance. J Diabetes Sci Technol. 2014;8(2):419-421.
  3. ISO. Medical devices – Application of risk management to medical devices. ISO 14971. Geneva, Switzerland: International Organization for Standardization; 2007.


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