The Architecture of Diagnostic Research: From Bench to Bedside-Research Guidelines Using Liver Stiffness as an Example

The diagnostic research process can be divided into five phases, designed to establish the clinical utility of a new diagnostic test-the index test. The aim of the present review is to illustrate the study designs that are appropriate for each diagnostic phase, using clinical examples regarding liver fibrosis diagnosed with transient elastography, when possible. Phase 0 is the preclinical pilot phase during which the validity, reliability, and reproducibility of the index test are assessed in healthy and diseased people. Phase I is designed to describe the distribution of the index test results in healthy people and its normal values. Phase IIA comprises studies designed to estimate the accuracy (sensitivity and specificity) of the index test in discriminating between diseased and non-diseased people in a clinically relevant population. Phase IIB studies allow the comparison of the accuracy of different index tests; Phase IIC studies aim to evaluate the possible harms of incorporating the index test in a diagnostic-therapeutic strategy. In phase III, diagnostic test-therapeutic randomized clinical trials aim to assess the benefits and harms of the new diagnostic-therapeutic strategy versus the present strategy. Phase IV comprises large surveillance cohort studies that aim to assess the effectiveness of the new diagnostic-therapeutic strategy in clinical practice. Conclusion: As common in clinical research, giving excessive weight to the results of single studies and trials is likely to divert from the totality of evidence obtained through the systematic reviews of these studies, conducted with rigorous methodology and statistical methods.