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Clinical Epidemiology:
Case Study: A Diagnostic Rule for Deep Vein
Thrombosis in Primary Care
The diagnosis of deep vein thrombosis, or DVT, has long been regarded as a serious challenge in clinical
practice. DVT occurs when a blood clot, or thrombus, forms within a vein in one of the legs. This typically
leads to a red, warm, swollen and painful leg. When this occurs in a person, concern then arises because
these clots can potentially break off and get stuck in a major artery in the lungs, leading to pulmonary
embolism, which can be fatal. As a result, DVT needs to be recognised and treated with anticoagulants
to prevent such a complication.

The generally accepted test, the “reference test”, to diagnose or exclude DVT, is compression
ultrasonography. However, this kind of testing is expensive and requires referral to a hospital. Referral
of all patients suspected of DVT isn’t very efficient: we know that currently only a small proportion of
patients referred for compression ultrasonography actually do have DVT. A diagnostic strategy, such as
one based on signs, symptoms and other more readily available tests, might be helpful to identify those
patients suspected of DVT with a high probability of DVT. These patients could then be referred for
ultrasonography. It might also help to identify those patients with a low probability of DVT and those
patients in whom DVT can be excluded and a referral for ultrasonography isn’t needed.

One such diagnostic strategy, based on a patient’s medical history, symptoms and signs and on levels of
D-dimer, a blood test, was developed in the hospital setting some years ago. This strategy is called the
“Wells rule” and it’s been applied widely in hospitals around the world. However, since most patients
with suspected DVT are managed in primary care, the performance of Well’s rule has been questioned
in this setting and evidence was found that the rule didn’t perform well in primary care: too many
patients with a low risk of DVT according to the Wells rule did in fact have DVT. Consequently, primary
care researchers set out to develop a new rule to be applied in that setting.

So how can this problem be studied in a diagnostic research setting? What are we actually aiming to
study, and what kind of evidence do we need to produce to actually solve the clinical problem? We can
start by defining our research question. We want to know what the best combination of tests is to
assess the probability of having DVT in patients suspected of DVT in primary care. The aim is then to
develop a rule to decide which patients should be referred for compression ultrasonography to diagnose
or rule out DVT.

Before we start thinking about how we‘ll conduct our study, we need to define exactly what kind of
information we want to collect.
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The domain of our research should be patients who are suspected of having DVT. As we’re interested in
developing a tool to help primary care practitioners, our research should also focus solely on patients in
a primary care setting.

And which tests should we perform in our study? Evidence from previous studies has suggested that
several patient characteristics are important, such as recent surgery or the presence of cancer, as well as
the results from physical examination, such as swelling or redness of the leg. We‘ll also need to apply
any other tests we aim to include, such as a point-of-care D-dimer test, to all of the patients in our
study.

Finally, an essential consideration is the method that will be used to determine the presence of DVT in
our study. Ultrasonography seems like a natural choice as it’s an effective diagnostic tool, but this
requires the all patients to be referred, and this may be a challenge in a study that includes hundreds of
patients. Moreover, compression ultrasonography isn’t an ideal reference standard since some DVTs
may be missed. For that purpose we can also follow the patients for a specific period of time, say 3
months, to see whether they develop DVT or pulmonary embolism. Any cases of DVT or pulmonary
embolism are then considered to already have had a DVT at the time they visited the primary care
practice. Such a 3-month period is often used in such diagnostic DVT studies to identify the remaining
patients in whom the diagnosis was present, in addition to those detected during compression
ultrasonography.

Now we need to decide on the best way to recruit patients and collect information on all diagnostic
determinants and the outcome.

Generally speaking, a cross-sectional design for data collection is the most appropriate design for
diagnostic research. This would certainly be a reasonable approach if we decide to determine the
presence of DVT by performing ultrasonography in all of the patients. A complication, however, arises
when we consider the accuracy of our reference standard. As mentioned, compression ultrasonography
doesn’t guarantee a conclusive result. For this reason we may decide to follow patients for a 3-month
period to detect additional diagnoses of DVT or pulmonary embolism. Despite this “follow-up” period,
our design can still be considered in some ways to be cross-sectional by nature, as this follow-up
information is applied to assess whether the diagnosis was present at the time of the primary care
consultation.

A final important note about the study design relates to the recruitment period. As with the cow milk
allergy example we discussed previously, we’ll need to conduct our study over a long period of time in
order to recruit enough patients. It may even take several years to collect enough information so that
we can draw reliable conclusions.

So now let’s assume that we‘ve conducted our study and we have a database with information about
the predictors and outcome for all of our patients. We need to convert this information into a useful
tool for future primary care practitioners.
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First we should select a set of candidate predictors that are likely to be useful in diagnosing DVT. The
new point-of-care D-dimer test should certainly be considered, as well factors that are known to be
related to DVT risk, such as age, sex, and clinical features such as swelling of the leg. We may also
consider other factors such as comorbidities and the use of medications such as oral contraceptives. We
can then include these factors in a logistic regression model, and fit the model to our patient data.

The result we obtain is a mathematical tool consisting of a set of values corresponding to each of the
diagnostic factors in our model. Ultimately, we need to distribute this tool in a form that’s easy to use
for clinicians. While some existing rules are based on simplified models, so probabilities can be
calculated by hand, we could decide to create an online calculator or app. We may also want to
designate cut-off values or thresholds, so that patients with a very high probability are referred for
ultrasonography to confirm a diagnosis of DVT, patients with a moderate probability receive further
testing, while patients with a very low probability can have DVT ruled out.

Research very similar to this has actually already been conducted, and several clinical decision rules for
DVT have been developed. But once again, the development of a diagnostic score is not the end of the
story. As we’ve seen in the field of DVT research, it takes many years to test the performance and
clinical utility of new rules. Additional studies have been performed in recent years and a rule to guide
diagnostic assessment in patients suspected of DVT in primary care has been included in current clinical
guidelines and is now widely applied in daily practice.