Blood cultures are the gold standard in the diagnosis of bacteremia and the timely and appropriate decision to initiate antimicrobial therapy that can save lives. Blood culture contamination, on the other hand, can cause a false positive that can result in a practitioner prescribing anti-biotics for an infection that does not exist.¹⁵ The risk of blood culture contamination is highest during specimen collection and blood culture bottle inoculation. The clinical laboratory is responsible for providing instructions regarding proper specimen collection procedures to those who draw and process the patient specimen and arrange for transport to the clinical laboratory. This example emphasizes several elements of the TTP that include specimen collection and preparation, testing, and engagement of laboratory and patient care professionals.

Procedures for specimen collection, detection, and reporting of blood culture contamination are codified in regulatory and accreditation processes and otherwise described in professional guidance.^16,17 Suboptimal collection volumes and blood culture contamination rates can be reported back to units where the samples were collected. This information can, in turn, be used to assess and modify blood culture collection practices to reduce blood culture contamination. Current guidance recommends these rates be no higher than 3%, and when best practices are followed, a target contamination rate of 1% is achievable.¹⁶

This example also illustrates the need for laboratory professionals to work with physicians, nurses, and others in the patient care setting to ensure proper specimen collection and bottle inoculation steps are followed. Blood culture collection and bottle inoculation can be optimized by working with an antimicrobial stewardship program that follows a team-based approach to ensure appropriate utilization of antimicrobials.¹⁵ Antimicrobial stewardship teams are now required by the Centers for Medicare & Medicaid Services to be active in hospitals and other health care settings.¹⁸ The team often includes infectious disease physicians, nursing managers, pharmacists, laboratory professionals, and infection control and prevention staff. These teams can foster quality improvement (QA) practices that minimize blood culture contamination and make sure that an adequate volume of blood is drawn to accurately diagnose bacteremia. Both of these QA practices can support appropriate antibiotic use. The expanded TTP offers these teams a framework for identifying steps of the testing process that can be subject to quality improvement efforts relevant to detecting and reporting blood culture contamination. These steps include test selection, specimen collection and transport, laboratory interpretation, and results reporting.

An increasing number of clinical laboratories use next-generation sequencing (NGS), which poses novel challenges across the TTP.¹⁹ This example focuses on elements of the TTP that cover engagement of clinical and laboratory professionals, including patient involvement, optimization of the test method, and data that support laboratory testing and the timeliness of decisions made by clinicians and patients.

The NGS analysis of a patient sample is typically a 2-step process.¹⁹ The first step is the laboratory analysis of the patient sample to produce a set of sequence reads. The second step is entirely computational and is designed to produce contiguous nucleotide sequences from the set of sequence reads. Additional computational analysis is then used to identify and classify any clinically relevant features.

The decision to use NGS is often predicated on the need to interrogate multiple genes or discriminate among pathogens. This element of test selection and bulleting optimally includes knowledge sharing among the patient, clinician, and laboratory professional. Knowledge sharing assists the patient in making an informed decision regarding whether to proceed with testing. Secondary findings of clinical relevance, independent of the indication for testing, may also be found using NGS, and how these findings are handled requires attention from the patient, clinician, and laboratory professional.²⁰ Similarly, when results are reported, correlating sequence findings with the needs of the patient often requires specialized expertise to place the uses and limitations of the test in the proper clinical context.²¹

As of 2022, many NGS tests were developed and operationalized as laboratory-developed tests within the clinical laboratory, not otherwise purchased or available as a test system. The design, validation, and use of NGS tests requires informatics expertise to ensure the computational phase of testing described above produces reliable results. Professional and regulatory guidance are available that support the quality and application of NGS clinical testing.^22–24

Data external to those derived from the testing process are essential in deriving a clinically relevant test result.^25–27 For example, the ClinVar database provides information that supports clinical assertions as to whether variants are benign, pathologic, or of unknown significance.²⁸ This correlates to the outer partial rings of the expanded TTP that support both laboratory testing and decisions made by health care providers and patients. This also reinforces the need for a workforce competent to use data appropriately in deriving a clinically relevant test result and interpretation of that result.

Next-generation sequencing and other genetic tests are a primary driver for precision or “personalized” medicine, defined as “an innovative approach that uses information about an individual’s genomic, environmental, and lifestyle to guide decisions related to their medical management” (see https://www.genome.gov/genetics-glossary/Precision-Medicine).

Pharmacogenetic tests inform drug selection and dosages appropriate for a given patient. The US Food and Drug Administration recognizes more than 60 pharmacogenetic associations for which data support therapeutic management recommendations (see https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations). Examples include the tests that inform the use of clopidogrel to reduce the risk of blood clots following stent placement and warfarin to identify patients at high risk for major bleeds.²⁹ The pharmacogenetic repertoire of an individual is highly dependent on their ancestry. As of 2022, our knowledge of clinically relevant pharmacogenetic variants is greatest for persons of European descent because this population was the focus for most of published studies. In turn, available pharmacogenetic testing is most applicable to these patients. Because less data are available for persons of non-European ancestral backgrounds, it can be challenging to detect clinically important pharmacogenetic genotypes in these patients.³⁰

Pharmacogenetic testing provides an example of the interplay among steps of the TTP, particularly test selection, sample testing, interpretation, and reporting. This is especially relevant to arriving at a test result that is analytically accurate and informative. For example, P450 2D6 is an enzyme, coded by the CYP2D6 gene, that influences the metabolism of a variety of clinically important drugs.³¹ The CYP2D6 gene is highly polymorphic, with sequence variations accounting for differences in drug metabolizer status. Incorrect polymorphic CYP2D6 assignments among several laboratories, documented through proficiency testing surveys offered by the College of American Pathologists, raised patient safety concerns related to drug choice and dosing based on test findings.³² These errors have been attributed to differences in test design, particularly with respect to what genotypes are detectable by a given method. To address these shortcomings, international workgroups developed recommendations for advancing the uniformity of pharmacogenetic test methods and result reporting.^33,34 Collaboration between laboratory and patient care professionals is essential in applying these and future guidance to inform clinical decisions regarding pharmacogenetic testing.