iPathology

More on Reference Ranges

I recently referred to an editorial in the Annals of Clinical Biochemistry that outlines ways to establish reference ranges and their attendant advantages and disadvantages. The authors of an editorial in January's Clinical Chemistry (55:15-17, 2009 [subscription required]) advocate "a new way of thinking about the relationship between biomarker measures and clinical decision-making". They envisage the use of lab results to generate a prediction of risk of disease, which actually sounds a lot like existing likelihood ratios. These predictions will be based on data other than simply a lab measurement, for example, they might include the patient's family and social histories, results of imaging studies, and even the patient's desire for treatment. A result might be of the form that given the results of the lab studies, imaging, history etc. the patient has X% risk of having heart disease, cancer, etc. Certainly I agree with the assessment that traditional reference ranges have important limitations. To move beyond reference ranges to presenting the clinician with more useful data, specifically data that integrate findings from the history, physical exam, imaging, treatment desires etc. will take a lot of effort, much of which will be informatics related.

"Rainbow Drawing"

 I first came across the term "rainbow draw" quite recently. It refers to the practice of drawing one of each blood tube type from a patient without a clear understanding of which tests are going to be performed. Some tubes have anticoagulants, of which there are there are several types (e.g., heparin, EDTA, citrate), some have serum separator gels, some are just plain tubes and so on. These tubes are recognizable by the different color of their caps and so the allusion to a rainbow. We use different tubes because some assays require serum (e.g., chemistry tests), some require anticoagulated blood (e.g., complete blood counts), some require plasma (e.g., coagulation assays) and so on.

A rainbow draw is a strange approach to sample collection! Some of these tubes are quite specialized, and it's unlikely that most patients would routinely need, for example, a tube collected for analysis of heavy metals. I understand that having to re-draw a patient is time consuming and perhaps uncomfortable for the patient, but drawing one of every tube is a waste of tubes, a waste of blood, and a substitute for rational thinking about which tubes are needed for different laboratory tests, and which tests are really needed.

Reference Ranges

An interesting editorial on the topic of reference ranges can be found in the January edition of the Annals of Clinical Biochemistry (46) 1-2, 2009, which also includes a couple of interesting papers on the approaches using "healthy" populations and real patient data. The editorial writer comments on these various approaches to defining reference ranges:

1. A classic based approach is to draw samples from a well defined cohort(s) of healthy people and typically take the middle 95% of values (mean +/-2 SD). This is required if there are variations between people of different age, gender, race etc. There are limitations to this approach: Who is healthy? Should there be a separate reference range for symptomatic people? How do we define ethnicity in populations that are composed of people of mixed ethnicity? For how long are samples stable prior to analysis?

2. The use of patient data to establish reference ranges. This may seem at first sight to be an odd way to establish a reference range. Almost by definition, patients have some health problems. On the other hand, many patients do in fact have concentrations of many analytes that are within the ranges found in healthy people. If one excludes the "outlier" values, it is possible to derive a reference range that at least approximates that seen in healthy individuals. The other objection to the use of patient samples is that there may be pre-analytical variation that is not seen in carefully collected samples used solely for the purpose of establishing a reference range. The answer to this objection is that "real" patient samples are usually drawn and transported under less than ideal conditions. If there is variation seen because of pre-analytic factors, then shouldn't it be reflected in the reference range?
A big advantage of using real patient data is that large numbers of data points are available and, importantly, from groups such as children, from whom it is generally extremely difficult to get samples to do a reference range study.

So we have a "purist" approach and a "pragmatist" approach to reference range establishment. (Yes, Laboratory Medicine has its own set of disputes!) Moreover, those are not the only ways to think about lab values that require a clinical response. Some people advocate Decision Limits. In a nutshell, these are values that trigger a clinical decision (e.g., a diagnosis or a therapeutic intervention). We talked about some of these in the context of cholesterol and glucose, and how those values that have clinical significance are not evident from a simple statistical analysis of the distribution of values in health or disease. These are what I refer to as a "reference range by committee".

When it comes to reference ranges, all of these different approaches need to be considered; there is no one approach that is clearly right or wrong in all circumstances.