Case–Control and Two-Gate Designs in Diagnostic Accuracy Studies

Abstract

Background:In some diagnostic accuracy studies, the test results of a series of patients with an established diagnosis are compared with those of a control group. Such case-control designs are intuitively appealing, but they have also been criticized for leading to inflated estimates of accuracy. Methods: We discuss similarities and differences between diagnostic and etiologic case-control studies, as well as the mechanisms that can lead to variation in estimates of diagnostic accuracy in studies with separate sampling schemes ("gates") for diseased (cases) and nondiseased individuals (controls). Results: Diagnostic accuracy studies are cross-sectional and descriptive in nature. Etiologic case-control studies aim to quantify the effect of potential causal exposures on disease occurrence, which inherently involves a time window between exposure and disease occurrence. Researchers and readers should be aware of spectrum effects in diagnostic case-control studies as a result of the restricted sampling of cases and/or controls, which can lead to changes in estimates of diagnostic accuracy. These spectrum effects may be advantageous in the early investigation of a new diagnostic test, but for an overall evaluation of the clinical performance of a test, case-control studies should closely mimic cross-sectional diagnostic studies. Conclusions: As the accuracy of a test is likely to vary across subgroups of patients, researchers and clinicians might carefully consider the potential for spectrum

Tuberculosis diagnostics trials: do they lack methodological rigor?

“…In case-control studies, researchers often recruit bacteriologically confirmed TB cases (often those with clear-cut, advanced smear-positive disease) and healthy controls. This approach has been termed a two-gate design, because cases and controls are not sampled from the same study base; instead, they are sampled from two different populations [25]. For the same index test, studies with the two-gate design using healthy controls have been shown to produce higher estimates of diagnostic accuracy compared with trials that recruit a cohort of consecutive patients (single-gate design) in whom the test is clinically indicated [8,24,25].…”

“…This approach has been termed a two-gate design, because cases and controls are not sampled from the same study base; instead, they are sampled from two different populations [25]. For the same index test, studies with the two-gate design using healthy controls have been shown to produce higher estimates of diagnostic accuracy compared with trials that recruit a cohort of consecutive patients (single-gate design) in whom the test is clinically indicated [8,24,25]. This is because the two-gate design with healthy controls results in the selection of subjects from the extreme ends of the clinical spectrum (spectrum bias) [8,24,25].…”

“…For the same index test, studies with the two-gate design using healthy controls have been shown to produce higher estimates of diagnostic accuracy compared with trials that recruit a cohort of consecutive patients (single-gate design) in whom the test is clinically indicated [8,24,25]. This is because the two-gate design with healthy controls results in the selection of subjects from the extreme ends of the clinical spectrum (spectrum bias) [8,24,25]. For example, meta-analyses on NAT for TB meningitis [14] and pleuritis [16] found that, on average, case-control studies produced twofold higher estimates of diagnostic odds ratios than cross-sectional studies.…”

Vascular endothelial growth factor (VEGF) and prostate pathology

“…Such comparisons however, are not clinically relevant since elevated tPSA is the most frequent indication for prostatic biopsy, and reflect limited-challenge-bias (16,17). A diagnostic test must be evaluated in a clinically relevant population, preferably in a consecutive series of individuals in whom the target condition is suspected (17).…”

The Thin Line Between Hope and Hype in Biomarker Research

“…Several used a two-gate or case-control design, which is known to generate inflated results (6). Most of these deficiencies can be remedied.…”