Sources of Variation and Bias in Studies of Diagnostic Accuracy

By P. Whiting, A. Rutjes, Johannes B Reitsma, A. Glas, Patrick M. M. Bossuyt, J. Kleijnen. Annals of Internal Medicine, 2004

836 citations recorded by the source corpus.

Diagnostic tests are of crucial importance in health care. They are performed to reduce uncertainty concerning whether a patient has a condition of interest. A thorough evaluation of diagnostic tests is necessary to ensure that only accurate tests are used in practice. Diagnostic accuracy studies are a vital step in this evaluation process. Diagnostic accuracy studies aim to investigate how well the results from a test being evaluated (index test) agree with the results of the reference standard. The reference standard is considered the best available method to establish the presence or absence of a condition (target condition). In a classic diagnostic accuracy study, a consecutive series of patients who are suspected of having the target condition undergo the index test; then, all patients are verified by the same reference standard. The index test and reference standard are then read by persons blinded to the results of each, and various measures of agreement are calculated (for example, sensitivity, specificity, likelihood ratios, and diagnostic odds ratios). This classic design has many variations, including differences in the way patients are selected for the study, in test protocol, in the verification of patients, and in the way the index test and reference standard are read. Some of these differences may bias the results of a study, whereas others may limit the applicability of results. Bias is said to be present in a study if distortion is introduced as a consequence of defects in the design or conduct of a study. Therefore, a biased diagnostic accuracy study will produce estimates of test performance that differ from the true performance of the test. In contrast, variability arises from differences among studies, for example, in terms of population, setting, test protocol, or definition of the target disorder (1). Although variability does not lead to biased estimates of test performance, it may limit the applicability of results and thus is an important consideration when evaluating studies of diagnostic accuracy. The distinction between bias and variation is not always straightforward, and the use of different definitions in the literature further complicates this issue. For example, when a diagnostic study starts by including patients who have already received a diagnosis of the target condition and uses a group of healthy volunteers as the control group, it is likely that both sensitivity and specificity will be higher than they would be in a study made up of patients only suspected of having the target condition. This feature has been described as spectrum bias. However, strictly speaking, one could argue that it is a form of variability; sensitivity and specificity have been measured correctly within the study and thus there is no bias; however, the results cannot be applied to the clinical setting. In other words, they lack generalizability (2). Others have argued that when the goal of a study is to measure the accuracy of a test in the clinical setting, an error in the method of patient selection is made that will lead to biased estimates of test performance. They use a broader definition of bias and take into account the underlying research question when deciding whether results are biased. In this paper, we use a more restricted definition of bias. Our goal is to classify the various sources of variation and bias, describe their effects on test results, and provide a summary of the available evidence that supports each source of bias and variation (Table 1). For this purpose, we conducted a systematic review of all studies in which the main focus was examine the effects of one or more sources of bias or variation on estimates of test performance. Table 1. Description of Sources of Bias and Variation Methods Literature Searches We searched MEDLINE, EMBASE, BIOSIS and the methodologic databases of the Centre for Reviews and Dissemination and the Cochrane Collaboration from database inception to 2001. Search terms included sensitivit*, mass-screening, diagnostic-test, laboratory-diagnosis, false positive*, false negative*, specificit*, screening, accuracy, predictive value*, reference value*, likelihood ratio', sroc, and receiver operat* characteristic*. We also identified papers that had cited the key papers. Complete details of the search strategy are provided elsewhere (3). We contacted methodologic experts and groups conducting work in this field. Reference lists of retrieved articles were screened for additional studies. Inclusion Criteria All studies with the main objective of addressing bias or variation in the results of diagnostic accuracy studies were eligible for inclusion. Studies of any design, including reviews, and any topic area were eligible. Studies had to investigate the effects of bias or variation on measures of test performance, such as sensitivity, specificity, predictive values, likelihood ratios, and diagnostic odds ratios, and indicate how a particular feature may distort these measures. Inclusion was assessed by one reviewer and checked by a second reviewer; discrepancies were resolved through discussion. Data Extraction One reviewer extracted data and a second reviewer checked data on the following parameters: study design, objective, sources of bias or variation investigated, and the results for each source. Discrepancies were resolved by consensus or consultation with a third reviewer. Data Synthesis We divided the different sources of bias and variation into groups (Table 1). Table 1 provides a brief description of each source of bias and variation; more detailed descriptions are available elsewhere (3). Results were stratified according to the source of bias or variation. Studies were grouped according to study design. We classified studies that used actual data from one or more clinical studies to demonstrate the effect of a particular study feature as experimental studies, diagnostic accuracy studies, or systematic reviews. Experimental studies were defined as studies specifically designed to test a hypothesis about the effect of a certain feature, for example, rereading sets of radiographs while controlling (manipulating) the overall prevalence of abnormalities. Studies that used models to simulate how certain types of biases may affect estimates of diagnostic test performance were classified as modeling studies. These studies were considered to provide theoretical evidence of bias or variation. Role of the Funding Source The funding source was not involved in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Data Synthesis The literature searches identified a total of 8663 references. Of these, 569 studies were considered potentially relevant and were assessed for inclusion; 55, published from 1963 to 2000, met inclusion criteria. Nine studies were systematic reviews, 16 studies used an experimental design, 22 studies were diagnostic accuracy studies, and 8 studies used modeling to investigate the theoretical effects of bias or variation. Population Demographic Features Ten studies assessed the effects of demographic features on test performance (Table 2) (4, 5, 7, 9, 11, 14, 15, 20, 22, 24). Eight studies were diagnostic accuracy studies, and 2 were systematic reviews. All but one study (22) found an association between the features investigated and overall accuracy. The study that did not find an association investigated whether estimates of exercise testing performance differed between men and women; after correction for the effects of verification bias, no significant differences were found (22). Table 2. Population In general, the studies found associations between the demographic factors investigated and sensitivity; the reported effect on specificity was less strong. Four studies found that various factors, including sex, were associated with sensitivity but showed no association with specificity (4, 5, 11, 20). The index tests investigated in these studies were exercise testing (5, 11, 20) to diagnose heart disease and body mass index to test for obesity (4). Two additional studies of exercise testing also reported an association with sensitivity, but the effects on specificity differed. One found that factors that lead to increased sensitivity also lead to a decrease in specificity (14); the second reported higher sensitivity and specificity in men than in women (16). A study of the diagnostic accuracy of an alcohol screening questionnaire found that overall accuracy was increased in certain ethnic groups (24). Sex was the most commonly investigated variable. Three studies found no association between test performance and sex, 9 found significant effects on sensitivity, and 4 found significant effects on specificity. Other variables shown to have significant effects on test performance were age, race, and smoking status. Disease Severity Six studies looked at the effects of disease severity on test performance (Table 2) (5, 11, 14, 19, 23, 25). Three studies were diagnostic accuracy studies, 2 were reviews, and one used modeling to investigate the effects of differences in disease severity. The modeling study also included an example from a diagnostic accuracy study of tests for the diagnosis of ovarian cancer (25). Three studies investigated tests for heart disease (5, 11, 14), one examined ventilationperfusion lung scans for diagnosing pulmonary embolism (23), and one investigated 2 different laboratory tests (one for cancer and the other for bacterial infections) (19). All 6 studies found increased sensitivity with more severe disease; 5 found no effect on specificity (5, 11, 14, 19, 23), and one did not comment on the effects on specificity (25). Disease Prevalence Six studies looked at the effects of increased disease prevalence on test performance (Table 2) (8, 10, 13, 17, 21, 26). One study used an experimental design (8); the other studies were all diagnostic accuracy studies. The te

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Citations in the corpus

STARD 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration (2016, background): “In those cases, the final classification may be guided by the index test result, and the reported accuracy estimates for the index test will be too high.(1) 2 27 Tests that require subjective interpretation are particularly suscep-”
Polyp Miss Rate Determined by Tandem Colonoscopy: A Systematic Review (2006, background): “This generally leads to inflated estimates of sensitivity and specificity of the test under evaluation (6).”
Systematic Reviews of Diagnostic Test Accuracy (2008, positive): “The methodological quality of the selected primary studies was assessed using pre-deﬁned criteria based on elements of study design, conduct and analysis which are likely to have a direct relationship to bias in a test accuracy study 30-32 .”
ENDPOINTS AND CLINICAL TRIAL DESIGN FOR NONALCOHOLIC STEATOHEPATITIS (2011, background): “Several reports provide guidance on how to avoid bias in such studies.(48,49) The generalizability of the results must be evaluated in rigorously performed independent validation studies in large, well-characterized, and independent cohorts in a variety of settings.”
Screening for Depression in Medical Settings with the Patient Health Questionnaire (PHQ): A Diagnostic Meta-Analysis (2007, methodology): “We assessed study quality in line with accepted guidelines.(25) In particular, we sought information on the application of a diagnostic standard independent of the knowledge of scores on the PHQ instrument (“blinded”).”
Evidence of bias and variation in diagnostic accuracy studies (2006, methodology): “These items were selected on the basis of recent systematic reviews of the available literature.(9,14,15) Table 1 displays 9 additional items that were selected to evaluate the quality of reporting.”
A review of solutions for diagnostic accuracy studies with an imperfect or missing reference standard. (2009, methodology): “In both situations there is a likely increase in agreement between index test results and reference standard outcome; these biases are known as incorporation and diagnostic review bias [8,11].”
Receiver operating characteristic (ROC) curve for medical researchers (2011, neutral): “Interested researcher can find detailed description of these and other biases such as withdrawal bias, lost to follow-up bias, spectrum bias, and population bias, elsewhere [22,23].”
Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. (2005, background): “Second, our understanding of how sources of bias and variability can affect estimates of diagnostic accuracy is largely based on thesemeasures [27,28].”
QUADAS-2: A Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies (2011, background): “The third review was an update on sources of bias and variation in diagnostic accuracy studies that included 101 studies (7).”
The use of receiver operating characteristic curves in biomedical informatics (2005, background): “[50] have performed a systematic review of these and many other sources of error, and they discuss the general effect that each has been found to have on test accuracy evaluation.”
Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies: The CHARMS Checklist (2014, background): “, blinded to) the results of the index tests is well established [35,40,54,69,79,80,85].”