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Six-Sigma - Medical Cutoffs as Tolerance Limits

See how quality-planning can deliver World Class Quality for a POC device. This QC application makes use of medical cutoffs as tolerance limits for a cardiac marker POC device. Using Six Sigma techniques, Dr. Westgard shows how QC can be easy for difficult methods. (Preview)

The definition of the tolerance limits is critical in Six Sigma Quality Management for the design of new processes, the assessment of performance of current processes, and quality control of current production processes. For analytical testing processes, several approaches have been advocated for defining tolerance limits or quality requirements of laboratory tests. The consensus conference on “Strategies to set global analytical quality specifications in laboratory medicine” recommended the following hierarchy of models for setting analytical quality specifications [1]:

1. Evaluation of the effect of analytical performance on the clinical outcomes in specific clinical settings.

2. Evaluation of the effect of analytical performance on clinical decisions in general:

a. Data based on components of biological variation.
b. Data based on analysis of clinician’s opinions.

3. Published professional recommendations.

a. From national and international expert bodies.
b. From expert local groups or individuals.

4. Performance goals set by

a. Regulatory bodies
b. Organizers of External Quality Assessment (EQA) schemes

5. Goals based on the current state of the art

a. As demonstrated by data from EQA or Proficiency Testing schemes.
b. As found in current publications on methodology.

It is important to understand that the different types of quality requirements may not be directly comparable [2]. For example, a clinical quality requirement (decision interval) often encompasses preanalytical and analytical factors of variation, whereas an analytical requirement encompasses only analytical factors; furthermore, an analytical quality requirement may encompass both imprecision and inaccuracy (allowable total error), or may be specific for either imprecision (allowable SD or CV) or inaccuracy (allowable bias).

“When available, and when appropriate for the intended purpose, models higher in the hierarchy are to be preferred to those at lower levels” [3]. This means that quality requirements for interpretation in a specific clinical situation are preferred over general clinical requirements, which in turn are preferred over professional recommendations, regulatory requirements, and state of the art performance. The ability to utilize clinical treatment guidelines as quality requirements is one of the important advantages of the clinical quality-planning model and the OPSpecs quality design and control tool. Here’s a good example of the use of medical cutoff points in the selection of QC procedures.

Quality requirements for cardiac markers

Cardiac markers is an area of laboratory testing that is “hot” in the the new millennium. So hot that the journal of Clinical Chemistry published its first theme issue on the topic “Heart Health” in March 2001. The lead editorial emphasized the redefinition of myocardial infarction on the basis of laboratory measurement of cardiac markers, particularly Troponin, and also recommended the use of CK-MB isoforms and myoglobin for early triage of patients [4].

Application of the consensus hierarchy of quality requirements to cardiac markers depends on the data and information available for the individual markers. The preferred approach is to use a specific clinical requirement that relates to the diagnostic application for myocardial infarction. Current recommendations on medical cutoff points can be used to define quality requirements for these tests. Here’s how.

Troponin I. Given a TnI cutoff of 0.40 ug/L, a measurement of this value should represent a medically important change from the normal amount of TnI that would be present in a healthly patient, which is very low and can be represented by the detection limit of the method or 0.09 ug/L. This difference of 0.31 ug/L, or 77% at the cutoff point, is the medically important change or clinical decision interval that needs to be correctly measured by the test method. This corresponds to a model 1 specification, or the highest model in the hierarchy, which is the preferred clinical quality requirement. The National Academy of Clinical Biochemistry’s (NACB) recommendation of a CV of 10% for all cardiac markers corresponds to a model 3 specification from a professional expert group [5].

Myoglobin. Given a Myoglobin cutoff of 100 ug/L and an upper limit of the reference interval for healthy individuals of approximately 50 ug/L, a clinical decision interval of 50 ug/L or 50% at the cutoff point describes the medically important change that must be detected by the test. This corresponds to a model 1 specification, or the preferred clinical quality requirement. The National Academy of Clinical Biochemistry’s (NACB) recommendation of a CV of 10% for all cardiac markers corresponds to a model 3 specification from a professional expert group [5].

CK-MB. Given a cutoff of 7.0 ug/L and an upper limit of the reference interval of 3.7 ug/L, a clinical decision interval of 3.3 ug/L or 47% describes the medically important change that must be detected by the test. The upper limit of the reference interval for males is somewhat higher, 4.3 ug/L, giving a decision interval of 2.7 ug/L or 39%. Both of these correspond to model 1 specifications. A general clinical quality requirement can also be described on the basis of biologic variation and is given as 31.2% by Ricos [6], which corresponds to a model 2 specification. The National Academy of Clinical Biochemistry’s (NACB) recommendation of a CV of 10% for all cardiac markers corresponds to a model 3 specification from a professional expert group [5].

 

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