Critical appraisal of diagnostic studies
Every day we find articles that show new diagnostic tests that appear to have been designed to solve all our problems. But we should not be tempted to pay credit to everything we read before reconsidering what we have, in fact, read. At the end of the day, if we paid attention to everything we read we would be swollen from drinking Coca-Cola.
We know that a diagnostic test is not going to say whether or not a person is sick. Its result will only allow us to increase or decrease the probability that the individual is sick or not so we can confirm or rule out the diagnosis, but always with some degree of uncertainty.
Anyone has a certain risk of suffering from any disease, which is nothing more than the prevalence of the disease in the general population. Below a certain level of probability, it seems so unlikely that the patient is sick that we leave him alone and do not do any diagnostic tests (although some find it hard to restrain the urge to always ask for something). This is the diagnostic or test threshold.
But if, in addition to belonging to the population, one has the misfortune of having symptoms, that probability will increase until this threshold is exceeded, in which the probability of presenting the disease justifies performing diagnostic tests. Once we have the result of the test that we have chosen, the probability (post-test probability) will have changed. It may have changed to less and it has been placed below the test threshold, so we discard the diagnosis and leave the patient alone again. It may also exceed another threshold, the therapeutic, from which the probability of the disease reaches the sufficient level so as not to need further tests and to be able to initiate the treatment.
Usefulness of diagnostic test
The usefulness of the diagnostic test will be in its ability to reduce the probability below the threshold of testing (and discard the diagnosis) or, on the contrary, to increase it to the threshold at which it is justified to start treatment. Of course, sometimes the test leaves us halfway and we have to do additional tests before confirming the diagnosis with enough security to start the treatment.
Diagnostic tests studies should provide information about the ability of a test to produce the same results when performed under similar conditions (reliability) and about the accuracy with which the measurements reflect that measure (validity). But they also give us data about their discriminatory power (sensitivity and specificity), their clinical performance (positive predictive value and negative predictive value), its ability to modify the probability of illness and change our position between the two thresholds (likelihood ratios), and about other aspects that allow us to assess whether it’s worth to test our patients with the diagnostic test. And to check if a study gives us the right information we need to make a critical appraisal and read the paper based on our three pillars: validity, relevance and applicability.
Let’s go with the critical appraisal of diagnostic studies
Let’s start with VALIDITY. First, we’ll make ourselves some basic eliminating questions about primary criteria about the study. If the answer to these questions is no, the best you can do probably is to use the article to wrap your mid-morning snack.
Was the diagnostic test blindly and independently compared with an appropriate gold standard or reference test?. We must review that results of reference test were not interpreted differently depending on the results of the study test, thus committing an incorporation bias, which could invalidate the results. Another problem that can arise is that the reference test results are frequently inconclusive. If we made the mistake of excluding that doubtful cases we’d commit and indeterminate exclusion bias that, in addition to overestimate the sensitivity and specificity of the test, will compromise the external validity of the study, whose conclusions would only be applicable to patients with indeterminate result.
Do patients encompass a similar spectrum to which we will find in our practice?. The inclusion criteria of the study should be clear, and the study must include healthy and diseased with varying severity or progression stages of disease. As we know, the prevalence influences the clinical performance of the test so if it’s validated, for example, in a tertiary center (the probability of being sick is statistically greater) its diagnostic capabilities will be overestimated when we use the test at a Primary Care center or with the general population (where the proportion of diseased will be lower).
At this point, if we think it’s worth reading further, we’ll focus on secondary criteria, which are those that add value to the study design. Another question to ask is: had the study test’s results any influence in the decision to do the reference test?. We have to check that there hasn’t been a sequence bias or a diagnostic verification bias, whereby excluding those with negative test. Although this is common in current practice (we start with simple tests and perform the more invasive ones only in positive patients), doing so in a diagnostic test study affect the validity of the results. Both tests should be done independently and blindly, so that the subjectivity of the observer does not influence the results (review bias). Finally, is the method described with enough detail to allow its reproduction?. It should be clear what is considered normal and abnormal and what criteria we have used to define normal and how we have interpreted the results of the test.
Having analyzed the internal validity of the study we’ll appraise the RELEVANCE of the presented data. The purpose of a diagnostic study is to determine the ability of a test to correctly classify individuals according to the presence or absence of disease. Actually, and to be more precise, we want to know how the likelihood of being ill increases after the test’s result (post-test probability). It’s therefore essential that the study gives information about the direction and magnitude of this change (pretest / posttest), that we know depends on the characteristics of the test and, to a large extent, on the prevalence or pretest probability.
Do the work present likelihood ratios or is it possible to calculate them from the data?. This information is critical because if not, we couldn’t estimate the clinical impact of the study test. We have to be especially careful with tests with quantitative results in which the researcher has established a cutoff of normality. When using ROC curves, it is usual to move the cutoff to favor sensitivity or specificity of the test, but we must always appraise how this measure affects the external validity of the study, since it may limit its applicability to a particular group of patients.
How reliable are the results?. We will have to determine whether the results are reproducible and how they can be affected by variations among different observers or when retested in succession. But we have not only to assess the reliability, but also how accurate the results are. The study was done on a sample of patients, but it should provide an estimate of their values in the population, so results should be expressed with their corresponding confident intervals.
The third pillar in critical appraising is that of APLICABILITY or external validity, which will help us to determine whether the results are useful to our patients. In this regard, we ask three questions. Is the test available and is it possible to perform it in our patients?. If the test is not available all we’ll have achieved with the study is to increase our vast knowledge. But if we can apply the test we must ask whether our patients fulfill the inclusion and exclusion criteria of the study and, if not, consider how these differences may affect the applicability of the test.
The second question is if we know the pretest probability of our patients. If our prevalence is very different from that of the study the actual usefulness of the test can be modified. One solution may be to do a sensitivity analysis evaluating how the study results would be modified after changing values of pre and posttest probability to a different ones that are clinically reasonable.
Finally, we should ask ourselves the most important question: can posttest probability change our therapeutic attitude, so being helpful to the patient?. For example, if the pretest probability is very low, probably the posttest probability will be also very low and won’t reach the therapeutic threshold, so it would be not worth spending money and effort with the test. Conversely, is pretest probability is very high it may be worth starting treatment without any more evidence, unless the treatment is very expensive or dangerous. As always, the virtue will be in the middle and it will be in these intermediate areas where more benefits can be obtained from the studied diagnostic test. In any case, we must never forget who our boss is (I mean the patient, not our boss at the office): you must not to be content only with studying the effectiveness or cost-effectiveness, but also consider the risks, discomfort, and patients preferences and the consequences that can lead to the performing of the diagnostic test.
If you allow me an advice, when critically appraising an article about diagnostic tests I recommend you to use the CASP’s templates, which can be downloaded from the website. They will help you make the critical appraising in a systematic and easy way.
A clarification to go running out: we must not confuse the studies of diagnostic tests with diagnostic prediction rules. Although the assessment is similar, the prediction rules have specific characteristics and methodological requirements that must be assessed in an appropriate way and that we will see in another post.
Finally, just say that everything we have said so far applies to the specific papers about diagnostic tests. However, the assessment of diagnostic tests may be part of observational studies such as cohort or case-control studies, which can have some peculiarity in the sequence of implementation and validation criteria of the study and reference test. But that’s another story…