Laboratory methods provide information for use in managing patients and addressing relevant clinical questions. The usefulness of a method depends on both the analytical performance and the clinical characteristics of the method (clinical sensitivity, specificity, and predictive value). These last factors are characteristic of the clinical application and not properties of the test. The clinical significance of a test should be defined in terms of the disease or syndrome that is the subject of the test. These include disease prevalence, possible outcome, and cost to the patients and others for incorrect information (false-positive and/or false-negative results). Validation of clinical utility of an assay is also a complex process that possesses many challenges. Clinical utility is ref-ered to here as the indications for use. For example, the assay is intended to quantify a nucleic acid (analyte) but is indicated for a certain clinical condition or scenario. The first step of the analytical verification is to formulate a clinical question and to identify the target population to which the test will be applied. There are three integral parts in formulating a clinical question: (1) defining the subject population, (2) defining the management decision that needs to be made, and (3) to identify the role of the method in decision-making. When the clinical use of each assay is being considered, it is assumed that the assay analytical performance characteristics are very well understood. Known analytical limitations (e.g., reportable range for quantifying, precision for nonclinical samples) should be taken into consideration when determining the clinical use for each particular assay. Clinical verification requires evaluation of the clinical sensitivity of the test by evaluating an appropriate number of samples from patients who have been diagnosed with the disease. The population and type of sample should be fully described because the results for a method in a given population using a specified sample type might not be suitable for another population, or even for another sample type within the same population. It is important to define the purpose indications for use of the method prior to starting the clinical verification. For example, indication for use of an assay could be diagnostic, population screening, or confirmatory. Clinical specificity can be determined by analyzing samples from patients diagnosed with a different disease that might be confused with the indicated disease and appears in the differential diagnosis. In addition, specimens from healthy donors can be appropriate for determining the clinical specificity of the test. The other parameters that need to be determined are the positive and negative predictive values, as well as a predictive value of the test over the course of disease or therapy. It is of general practice for a clinical laboratory to determine sensitivity and specificity of a new assay by comparing the new assay with a gold standard method or a method currently used in the laboratory. In some instances, molecular tests have appeared to be more sensitive or specific than current gold standard tests. Resolution of discrepancies between the new and currently used or gold standard methods can pose some challenges. In a number of instances, using a different molecular method has resolved discrepancies. Furthermore, in order to determine the clinical utility of a new LDA, variables that could affect results and their interpretation should also be considered. Some of these variables could be assessed for infectious disease testing, like microbial host interactions, microbial dynamics, variants and mutations, replicative fitness of the microbial agent, and so forth.
It is important to point out that data generated during the clinical verification of each assay should be gathered and kept organized to satisfy the requirements by the different regulatory bodies. These user-generated data should be filed and maintained according to the certifier's criteria. Within the documentation, the laboratory should have available a list of indications for which the assay has been verified (Table 3).
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