1. Purpose of laboratory test requests (screening, diagnosis, differential-diagnosis, validation, monitoring).

This topic requires understanding of sensitivity, etc., which is explained in topic 3.

Purpose of investigation

When one orders a test (laboratory, imaging, or otherwise), it's important to have a predetermined purpose for the test and not just ordering tests willy-nilly. Tests are often invasive as well as time-consuming and expensive, and so they should be worth the risk, time, and expense. There is no point in ordering a test if the test result does not influence how you approach the patient.

Generally, investigations can be used for:

• Screening
• Diagnosis
• Follow-up/monitoring
  • Monitoring progression/response to treatment
• Evaluation of prognosis
  • Information regarding the likely outcome of the disease

Value to the patient

An investigation should have some form of value for the patient (except if done in a research setting or for epidemiological purpose, in which case the investigation has value for researchers, and in turn, future patients). The value to the patient should also weigh up for any negative consequences of the investigation.

Frail patients

Many frail patients, especially elderly, cannot or do not want to undergo certain tests or invasive procedures. Is there, for example, a point in evaluating a frail elderly person for cancer, if they do not want to or cannot undergo cancer treatment anyway? Take the following example:

A frail elderly patient living in an institution (like a nursing home) has a positive faecal occult blood test. The physician considers to refer them to colonoscopy, but stops to consider: how will a colonoscopy be of value to the patient? In their current state, even if the colonoscopy would show colorectal cancer, the patient would not be a candidate for any surgery or chemotherapy, so even if a diagnosis is made, nothing will change for the patient (except the stress of knowing they have cancer). In addition, colonoscopy is an invasive investigation which requires strict patient preparation, which can be difficult for a frail elderly to perform or even survive.

If they have colorectal cancer and it grows and eventually causes intestinal obstruction, colonoscopy may be indicated for stenting the bowel, in which case the colonoscopy would have value for the patient as palliative therapy. As such, one could note that the patient may have colorectal cancer, and only refer them to colonoscopy if intestinal obstruction is suspected at a later time.

One can also argue that even performing a faecal occult blood test in this case has no value for the patient, because the next step after a positive test would be a colonoscopy, a procedure which would not be of value to the patient anyway.

Patient management is the same regardless of test result

In some cases, it may be temping to order an investigation to gain more information, but it's important to consider whether that information is of value or not. Take the following example:

A young male has had lower back pain for a few days. The pain is not severe, and there are no red flags for cauda equina syndrome. He wants an MRI to know what's going on, but the physician stops to consider: how will an MRI be of value to the patient? The patient may or may not have a herniated disc, but even if they do, a herniated disc without red flags isn't an indication for surgery anyway. As such, whether the MRI shows a herniated disc or not, the management will be the same (no surgery, only physical therapy and pain relief), and the MRI is therefore of no value to the patient (and it is resource-intensive).

On the other hand, if the patient has debilitating pain or there are red flags present, he may have cauda equina syndrome, in which case surgery is indicated. In this case, MRI has value: it determines whether they need surgery or not.

Another example:

A middle aged woman has symptoms of an upper respiratory tract infection. After taking the anamnesis and physical examination, you're certain that it's a viral infection. You reflexively want to order a CRP or leukocyte count, but you stop to consider: will the laboratory investigation likely be of value to the patient? You know that viral URTIs only cause mildly elevated inflammatory parametres, so that's likely what you'll find anyway. And even if the CRP is higher than you expect, you're certain enough that this is not a bacterial infection, so you won't be administering antibiotics anyway. So even after making the investigation, you'll most likely not be changing your management of this patient; managing their symptoms and encouraging rest, without antibiotics.

On the other hand, if the patient has symptoms which make it difficult to distinguish between viral and bacterial infection clinically, a laboratory investingation is merited, as it provides additional information which can aid in the diagnosis and therefore the treatment in this case.

Consider that many laboratories can analyse a pharyngeal swab for specific airway viruses. Would making such an investigation in this case change the management of the patient? In most cases no, as there is no specific treatment for most airway viruses anyway.

Diagnosis

When an investigation is ordered for diagnosis, one should already have a list of differential diagnoses before ordering the test, and the test should be able to narrow down the list of differential diagnoses. It's important to consider the test's specificity, sensitivity, positive predictive value, and negative predictive value in this. There is no reason to perform an investigation if it doesn't help narrow down the number of differential diagnoses or doesn't validate your tentative diagnosis.

This article leans heavily on statistical terms like probability and thresholds. In real-life, the exact probability and thresholds cannot be known in most circumstances. Instead, we think of these factors in approximate terms based not on statistical analysis but our own experience and knowledge.

Approach to diagnosis

When a patient is presented with symptoms or clinical findings, one should formulate a list of differential diagnoses which could be underlying. Often, this is not a conscious process but rather an unconscious one.

The model "a safe diagnostic strategy", made by professor John Murtagh, involves five questions one should ask themselves during patient presentations:

• What is the list of differential diagnoses, and which ones are most likely?
• Which life-threatening or severe disorders are on the list of differential diagnoses that must not be missed?
  • Or "are there any red flags?"
• Which disorders, which may present similarly, are usually overlooked?
  • Or "are there any diagnostic pitfalls I must avoid here?"
• Could the patient have one of the "great imitator" disorders? (Syphilis, tuberculosis, Lyme disease, SLE, +++)
• Is the patient actually trying to tell me something else that I'm missing?

Using clinical findings and anamnesis to evaluate the pre-test probability

The probability of a person having a certain disorder depends on their symptoms and signs. For example, a person with sore throat and swollen tonsils with exudate have a much higher probability of having streptococcal tonsillitis than a person with sore throat but normal tonsils. Therefore, performing physical examination and taking a thorough anamnesis before considering whether to do a test is important. In some cases, a good physical examination and anamnesis may increase the pre-test probability to such an extent that the test becomes unnecessary.

For some disorders, researches have designed risk stratification tools which can help us determine the pre-test probability systematically. Examples are Wells criteria for DVT and PE, Centor criteria for streptococcal pharyngitis, Alvarado score for acute appendicitis, and CHA2DS2-VASc score for thromboembolism in atrial fibrillation. These scores can give us the estimated pre-test probability in percent; for example, a CHA2DS2-VASc score of 3 equals a risk of thromboembolism of approximately 4.6%.

Considering test sensitivity

Using a test with low sensitivity for the diagnosis of a disorder can lack value. Consider, for example, a rib fracture. One might think that a rib fracture should be evaluated with a radiograph, as most fractures are evaluated. However, a radiograph has very low sensitivity for rib fracture (60%), and so 40% of people with rib fracture will have no findings on an x-ray. Knowing this, you could not trust a negative radiograph to rule out rib fracture, and so it is not recommended for the evaluation of this disorder.

Considering how pre-test probability changes the test characteristics

Because positive and negative predictive values of a test depend on the pre-test probability, test may become more or less useful as the pre-test probability changes.

For example, a negative D-dimer has a high negative predictive value for VTE. However, negative predictive value decreases with increasing pre-test probability. A person with a high pre-test probability (Wells score for PE of 7 or more) have a 40+% pre-test probability of PE. If the patient has a high pre-test probability, determined by their Wells score, the patient no longer has the same pre-test probability as the general population (which is low). The negative predictive value decreases, which makes a negative D-dimer unsuitable for ruling out PE in a person with high pre-test probability. In other words, a patient with a high Wells score but a negative D-dimer still has a relatively high probability of having PE.

Considering pre-test probability and disease severity

The more severe the suspected disorder is, the lower the pre-test probability needs to be before one should consider testing for it. This is because the consequences of missing a diagnosis is more severe, so the disadvantages of the test are weighed up for.

For example, one would not test every person with a sore throat for streptococcal tonsillitis, only if the pre-test probability is sufficiently high, usually more than 30%, as determined by a Centor score of 3 or more. However, one would test every person with significant microscopic haematuria for bladder cancer (usually by cystoscopy), despite a pre-test probability of only 5% (only 5% of people with significant microscopic haematuria have bladder cancer).

Considering the treatment threshold

The treatment threshold is a theoretical level of disease probability (pre-test or post-test) where the disease is so likely that you would consider treatment to be indicated. Another way to think of it is "at what degree of disease uncertainty am I comfortable with initiating treatment?".

The treatment threshold is low if the treatment is harmless for healthy people and very efficacious for people with the assumed disease, for example antihistamines in suspected allergic rhinitis.

The treatment threshold is high if the treatment is harmful for healthy people or it is not very efficacious for people with the disease. This can occur for example in case of cancer (where treatment is very harmful, so the disease probability should be close to 100% before considering treatment) or in case of bacterial infections which are usually uncomplicated and self-limiting (like uncomplicated acute otitis media or acute sinusitis).

If, based on the clinical findings, you find the pre-test probability to be sufficiently high that even a negative test will yield a post-test probability higher than the treatment threshold, testing does not influence the outcome, and so testing is unnecessary.

Alternatively, if you find the pre-test probability to be so low that despite a positive test the post-test probability remains lower than the treatment threshold, testing also does not influence the outcome, and so testing is unnecessary in this case as well. An example of this can be if a patient has a sore throat but you find no evidence of streptococcal tonsillitis, in which case even a positive rapid strep test won't make the diagnosis of streptococcal tonsillitis high enough that you would consider antibiotics.

Follow-up and monitoring

Follow-up and monitoring of a disorder is also a common use of laboratory and imaging investigations. Examples include:

• Serial CRP or leukocyte count following antibiotic prescription to evaluate the treatment response
• Serial plasma sodium measurement following fluid restriction in assumed SIADH
• Yearly brain MRI following removal of a meningeoma, to try and catch a recurrence early, before it causes symptoms

However, it's important to keep in mind the requirement of value for the patient. In the first scenario, there is value as a lack of normalisation of inflammatory parametres in a patient treated with antibiotic for a bacterial infection may be a sign that the antibiotic is ineffective, which may require administration of a different antibiotic. In the third scenario, there is also value, as the earlier one can catch recurrence of a meningeoma, the better the prognosis after treatment. However, if the patient is in a condition where they will not receive treatment anyway (for example, if they are preterminal), monitoring is not of value to the patient.

Evaluation of prognosis

In some cases, performing an investigation even though it won't change patient management can be useful if it provides information on patient prognosis, for example the life expectancy. This is most common in case of patients with cancer.

External resources

• Explaining laboratory test results to patients: what the clinician needs to know

Screening

Screening refers to using an investigation to detect a disease which has not yet caused symptoms, so-called subclinical disease, with the aim of initiating management as early as possible, to improve the prognosis. Examples include:

• Regular mammography or cervical cytology in women
  • Used to detect early or precursor breast cancer or precursor stages for cervical cancer, respectively
• Faecal occult blood test in middle-aged/elderly
  • Used to detect early colorectal cancer or bleeding colon polyps
• Screening for inborn errors of metabolism and developmental dysplasia of the hip in newborns
• Non-invasive prenatal test (NIPT) for trisomies during pregnancy

Screening is indicated if the disorder has a high mortality or morbidity, and there is treatment available. Like most things in life, screening is only viable if it can be proven that the advantages weigh up for the disadvantages.

Screening tests

A screening test is most useful when it has high sensitivity. It would be great if a screening test also had high specificity, but there is often a trade-off between sensitivity and specificity. Therefore, most screening tests have low specificity. As a result, screening tests produce few false negatives but many false positives, and many more false positives than true positives.

Because many of those who have a positive screening test are false positives, positive screening test must always be confirmed by a more specific test.

Advantages of screening

Screening may have many advantages. The main advantage, and the intention behind screening, is that treatment can be started at an earlier time, before symptoms even appear, which usually improves the prognosis considerably, and may allow for curative treatment, which may not have been an option if the disorder was not diagnosed at the asymptomatic stage.

Most national screening programmes are backed up by evidence that they reduce mortality or morbidity. For example, breast cancer screening reduces risk of dying from breast cancer by approximately 20-30%.

Disadvantages of screening

Unfortunately, screening has many disadvantages as well.

Low specificity of tests causing worry and more testing

Because screening tests necessarily have low specificity, there will be many false positives. Testing positive on a screening test, especially for cancer, leads to considerable worry for a person. Considering that most people who test positive on a screening test is false positive, the positive predictive value is low as well, meaning that the chance of having the disorder when testing positive is low. This concept is very difficult for laypeople to understand.

Because screening tests must be confirmed by a confirmatory test, screening for a disease always leads to more testing. In many cases, these tests are invasive, either entailing radiation exposure (CT scan) or complicated patient preparation and discomfort during the procedure (colonoscopy). In some cases, for example with NIPT testing, the confirmatory test (amniocentesis or chorionic villus sampling) is invasive and increase the risk of harm (abortion of the foetus in this case), which may lead to harm for people who are actually healthy.

Early diagnosis may not always improve prognosis

It is reasonable to assume that early diagnosis always improves the prognosis, but that is not always the case. In many cases, the cancer would develop so slowly that the person would never have known of it, or possibly only developed mild symptoms. However, cancer diagnosis almost always leads to aggressive treatment, which has its own effects on quality of life.

This is especially important for prostate cancer, for example. Prostate cancer is relatively common in elderly, but research has shown that many who are treated for subclinical prostate cancer would never have developed symptoms of the cancer, and would rather have died peacefully, never knowing that they even had the cancer. Also important to consider that cancer treatment causes significant reduction in quality of life, which is especially unfortunate if the cancer would never have caused symptoms anyway.

South Korea started screening for thyroid cancer in the late 20th century. Up until relatively recently, research showed that, while the incidince increased significantly (more cases of thyroid cancer were discovered), the mortality remained the same. In other words, screening detected more cases and lead to more people being treated for cancer, which is a burden to both the healthcare system and the individual, but screening could not demonstrate a reduction in mortality, which is arguably one of the most important goals of screening. This shows that screening can lead to significant overdiagnosis.

In Norway, it is estimated that for every 6 case of breast cancer that is discovered due to screening, 1 of those cases are overtreated, meaning that the cancer in that one case would not have needed treatment if it wasn't screened for.

Disorders are often rare, which reduce the predictive value

As already established, pre-test probability influences the predictive value of a test. In asymptomatic people (the target population of screening tests), the pre-test probability is equal to the prevalence of the disorder. The disorder we screen for often have a very low prevalence; for example, breast cancer has a prevalence of 0,4%.

Because the disorders we screen for is so rare, the positive predictive value decreases.

A negative screening test does not guarantee absence of disease

Even though most tests used to screen populations have high sensitivity and therefore a low rate of false negatives, false negatives still occur, giving many people the impression that they do not have a disorder when they do. This may lead to them not seeking healthcare for new symptoms which are actually due to a disorder, because they think the screening test has cleared them.

Screening a population is expensive

For screening to be effective, it needs to screen many people, usually many thousands. This is expensive, money which could be used to research other fields of medicine.