Likelihood Ratio Approach and Clinical Interpretation of Laboratory Tests

Laboratory tests are an important component in the diagnostic process. From an analytical point of view, most tests have reached high technical standards resulting in quantitative results with very high precision and accuracy. The challenge for the clinician then is how to interpret those results. It is particularly difficult when different test systems use different scales and arbitrary units for a given biomarker, as is often the case in immunologic testing. For the clinician it is demanding to estimate the predictive value of a diagnostic test result. A solution to this problem that is advocated here is to provide likelihood ratios as a measure of the predictive value of test results. This approach is not only useful to harmonize interpretation between assays and assay platforms but can be employed as well in external quality control programs. However, the concept of likelihood ratios in clinical diagnostics, although not new, is not yet generally accepted and needs further promotion by demonstrating its usefulness. Some 55 years ago, a “technic for the estimation of the predictive value of diagnostic test results in the subject tested when the sensitivity and specificity of the test and the prevalence of the disease in the population are known” was described (1). At that time, the technic was limited to dichotomous, qualitative test results. Later, the approach has been extended to intervals of test results and their likelihood ratio (LR) (2–6). The LR of a diagnostic test result is defined by its likelihood in diseased subjects (sensitivity) versus non-diseased subjects (1-specificity). In the field of autoimmunity, test result interval-specific LRs have been applied for the diagnosis of rheumatoid arthritis (7, 8), vasculitis (9, 10), systemic rheumatic diseases (11–16), inflammatory bowel disease and celiac disease (17–22). It has been realized that expressing results in the form of LRs provides a convenient way to harmonize test results which otherwise would be expressed in various units and provider-defined scales, making it difficult to compare results. This has led to a proposal for harmonization of anti-neutrophil cytoplasmic antibody (ANCA) testing (23, 24), antinuclear antibody testing (25, 26) and autoimmunity tests in general by reporting test result-specific LRs (27, 28). The calculation of LRs of test result intervals has been further extended to arbitrary quantitative test results (29, 30) and applied, for example, for the diagnosis of Alzheimer’s disease (31), ANCA testing (24), antinuclear antibody testing (26) and celiac disease (22). For the clinician, LRs could be a valuable diagnostic measure (32–35). Nevertheless, a wide application of LRs in diagnostic laboratory testing is not observed today. This might have different reasons, such as: a LR is related to a specific diagnosis and, habitually, the clinician does not inform the testing laboratory on the precise diagnostic question. a test might be used for screening purposes resulting in a differential diagnosis. there is a dearth of data on LRs (and consequently laboratories do not report LRs). With regard to the differential diagnosis, it should be noted that LRs for each differential diagnosis are very valuable to estimate the relative weight of possible diagnoses (36, 37). Establishing LRs needs clinical studies to be performed, either by the in vitro diagnostics industry, the laboratories, or a collaboration of both. As this has a cost, reimbursement of laboratory tests should consider the additional clinical value of the diagnostic information given by the LR (38), which is not the case today.