Establish and Maintain a Compliant Body Fluid Testing Program


March 2018 - Vol. 7 No. 2 - Page #2

Medical laboratories of all types and sizes must continually navigate the regulatory requirements for performing clinical testing, and the controversies surrounding the measurement of chemistry analytes in body fluids is no exception. This wide range of fluids includes pleural, peritoneal, pericardial, cerebrospinal fluid (CSF), and synovial fluids, as well as amniotic fluid and saliva, sweat, semen, and stool. Given that details on specific body fluids often are not included in assay manufacturers’ intended-use claims, when body fluids are tested using these assays, the assays are considered modified or laboratory-developed tests and, as such, are subject to further regulatory scrutiny.

In order to negotiate these realities, the laboratory must work to develop an appropriate test menu with corresponding validation plans in order to properly provide body fluid testing in support of clinical need. In the course of developing the validation plans, laboratory leadership should work with clinicians to assess their needs and desires for results reporting content and interpretation. The clinical application and utility of body fluid analyte measurement is significant, and a full understanding of this is necessary to the clinical laboratory total testing process.

Accreditation Challenges

Clinical laboratories often maintain licensure via an accreditation agency with deemed authority under the Clinical Laboratory Improvement Amendments (CLIA) such as the Commission on Office Laboratory Accreditation (COLA), The Joint Commission, or the College of American Pathology (CAP). To further complicate matters, the accreditor’s checklists are revised every year in an attempt to continually clarify operational expectations. However, significant gray area remains regarding the extent to which body fluid tests should be validated, which tests should be considered routine and orderable, how a clinically unique test should be handled, and the best way to provide reference ranges and appropriate interpretative information to clinicians in a meaningful way. Due to a lack of clear guidelines in these areas, labs continue to be cited for noncompliance.

Based on existing clinical evidence for body fluid test utility and work done in this field—including at Mayo Clinic in Rochester, Minnesota—there is now hope that more certainty and less trepidation will exist when laboratories perform body fluid validation, testing, and result reporting than in the past.

Necessity of Body Fluid Validation

Controversy:

Body fluid validation must meet regulatory standards, and accreditors state which validation studies are needed, such as accuracy, precision, reporting range, and interferences. However, it is then up to each laboratory to decide which fluid type and analyte combinations need to be validated, and ultimately how these tests will be orderable by providers.

Solution:

Tests on body fluid sources with the highest clinical utility merit validation as these are tests that contribute the most value to patient outcomes. Health care providers rely on the accuracy of these results to determine a diagnosis or treatment path. Laboratories can go to extreme efforts to validate body fluid tests or they may opt to take a more minimalist approach. Either way, a risk-based approach is best to justify actions (or lack thereof) when deciding how many samples to include and the number of data points to gather for any given study.

Be sure to remain cognizant of the risks of neglecting to fully and completely perform an extensive validation on every body fluid. The obvious risk is every clinical laboratorian’s worst fear: Reporting an inaccurate result that could lead to patient harm. Therefore, every effort should be made to minimize that risk. Fortunately, published work demonstrates a lack of matrix effects on the recovery of many analytes in a range of body fluids tested, using two instrument manufacturers.1,2 Published literature is an advantageous resource when developing a validation plan. One might choose to reduce the number of samples and/or replicates if there is published evidence supporting that decision. However, do not oversimplify this rationale. For example, it is not acceptable to assume any serous body fluid will behave identically as serum such that the same interference limits for hemolysis can be used. In actuality, the interference limits will be impacted, owing to the differences in expected concentrations, the decision limits affecting interpretation of results in each body fluid compared to serum, and also among different body fluid types.

Should Reference Ranges Be Supplied?

Arguably, the most challenging CAP checklist item is defining a reference range for “routine orderable tests.” For some tests, this is a practical solution, but for many others, it is not.

Controversy:

Use of the term “reference range” typically implies a statistically defined grouping of laboratory test results measured in a healthy population. However, this is not helpful when applied to body fluids given that in almost all cases, they are not acquired from a healthy person. Rather, these fluids only accumulate to a volume capable of being aspirated as part of some pathological illness. While there are a few exceptions of higher-volume fluids that exist in a healthy body, such as amniotic fluid during pregnancy and cerebrospinal fluid (CSF), obvious ethical concerns remain regarding the collection of specimens simply for a normal donor study. A laboratory would likely have a difficult time gaining permission from its institutional research review board to conduct such a study. Meanwhile, there are published pericardial fluid reference intervals reported from the collection of fluid from patients who underwent open-heart surgery.

Solutions:

A critical appraisal leads to further questions, including: Should pericardial fluid still be considered a “normal” sample if collected from patients undergoing open-heart surgery? Further, what is the use if normal versus abnormal is not clinically differentiated? Thus, the provision of reference ranges remains arguable and ethnically controversial.

Given these realities, what can labs do to close this gap? One option is to use the manufacturer’s citation. There are a few tests that are included in the manufacturer’s package insert for measurement of an analyte in specific body fluids. One example is CSF total protein, which has been FDA-approved by many manufacturers and lists expected concentrations. In the same category, one could also consider reporting interpretive information such as clinical decision limits with results based on published studies. For example, a result comment aiding in the interpretation of pleural fluid protein to serum protein concentration ratios for differentiating transudative and exudative effusions could be reported in lieu of an actual reference interval, and would likely prove far more valuable for interpretation.

Verification of Published Body Fluid Decision Limits and Reference Intervals

Controversy:

The published body fluid studies (including those cited by manufacturers’ package inserts) often have ill-described method sections. Thus, the preanalytical and analytical details are not well known, and transference is risky business. Many assays used to measure analytes in body fluids are not well harmonized, so even if the methods are described, unless yours is identical, it may be of limited use. Also, some of the best studies are dated, and assays can drift from one lot of reagent to the next. Who can even begin to speculate how a manufacturer’s method for measuring a particular analyte may have varied over decades? And, how do these methods account for various generations of reagents and instruments? Are you nervous yet?

Solutions:

A prospective study performed in collaboration with the clinical and procedural area is about as close to a gold standard approach as one can get. However, such a process is often resource-intensive and cost-prohibitive. A retrospective study to correlate the clinical and laboratory findings may be easier, particularly if the number of charts needing review is limited and methods for reporting results have been consistent over time. The lab may decide that the samples are just too precious, the volume too limited, and clinical studies simply are not practical. Therefore, use of the published reference intervals or decision limits will be used without further verification. Finally, a laboratory may choose to refrain from testing body fluids entirely, particularly for those types and analytes in which evidence of utility is weak or turnaround time is less critical.

The Overreaching Controversy

It is easy to appreciate why many in the field would argue that having to perform analytic validation is an incredible burden on laboratories. However, it is also easy to appreciate that labs must at least make an effort. Development of an appropriate test menu and a validation plan allows laboratories to confidently offer a body fluid test that supports clinical needs. Laboratories should also engage clinicians to offer valuable insights on how results are used and what information would be helpful in result reports. Ultimately, clinical laboratories should be aware of the total testing process and consult resources that critically review the clinical application and utility of analyte measurement in body fluids (see SIDEBAR).

References

  1. Owen WE, Thatcher ML, Crabtree KJ, et al. Body fluid matrix evaluation on a Roche Cobas 8000 system. Clin Biochem. 2015;48:911-914.
  2. Lin MJ, Hoke C, Dlott R, et al. Performance specifications of common chemistry analytes on the AU series of chemistry analyzers for miscellaneous body fluids. Clin Chim Acta. 2013;426:121-126.

Darci R. Block, PhD, DABCC, is co-director of central clinical laboratory and laboratory services in the department of laboratory medicine and pathology at Mayo Clinic in Rochester, Minnesota.

Christoph Bahn is a freelance writer for Mayo Medical Laboratories, specializing in clinical research and discovery.


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