Overdiagnosis and reference ranges ... again.

Here are our reference ranges for adult patients for a number of common analytes

	Low	High
Na	133	146
K	3.5	5.3
ALP	30	130
BIL	0	21
ALT	0	33
ALB	35	50
Prot	60	80
Visc	1.5	1.72
CRP	0	5
TSH	0.27	4.2
Hb	115	160
WBC	4	11
Plt	150	400

Looking at an adult primary population, the percentage of specimens with results outside these ranges are :

	Low	High
Na	3.2%	0.5%
K	1.2%	3.4%
ALP	0.3%	8.0%
BIL	0.0%	3.5%
ALT	0.0%	13.3%
ALB	2.0%	2.4%
Prot	1.3%	2.1%
Visc	1.7%	31.0%
CRP		34.0%
TSH	5.0%	13.0%
Hb	10.0%	8.3%
WBC	4.4%	5.6%
Plt	6.9%	4.2%

Now it is certainly true that this mixes up the pathogenic and the non-pathogenic. But it is surely also true that for most common tests that are carried out in primary care, most will be "normal". Or at least will be giving us very little diagnostic information. If a high proportion of the results are abnormal then the balance between sensitivity and specificity is almost certainly wrong. Do we really know the benefit of labelling a substantial proportion of a population abnormal? This appears to be a particular problem for tests we know are hard to interpret : ALT, ALP, TSH, inflammatory markers. With evidence that laboratory testing is helping drive an epidemic of overdiagnosis.

These are what the reference limits would be if we were to make just 5% of population "abnormal"

	Low	High
Na	133	144
K	3.7	5.3
ALP	44	189
BIL	0	23
ALT	7	70
ALB	36	49
Prot	62	80
Visc	1.51	1.99
CRP	0	85
TSH	0.08	8.89
Hb	96	161
WBC	3.69	13.1
Plt	122	444

Clinically this makes more sense. I have learned to ignore ALTs below 70. I don't worry about CRPs below 100. This is not to say that patients with an ALT below 70 don't have liver disease, or that a patient with a CRP below 85 doesn't have an inflammatory condition. This is why we still need clinical skills. It's just about thinking about when the test alone should prompt action - and this is how I think the reference range should be used.

The haematology results here are interesting. The platelet and white cell cut-offs suggested do fit better with clinical feeling. Not sure if there is evidence on haemoglobin. Because this is what we really need - what is the predictive power of a test for specific pathologies?

Creatinine shows a way forward here. The absolute clinical value of creatinine is low. But acute kidney injury flags based on relative changes feel clinically useful. 2.6% of renal function tests from primary care generate an AKI flag. This then might be a better way of thinking about normality. But unless we are very sure we know the benefit of reference ranges that medicalise large swathes of the population, I will continue to argue for wider limits.

ALT reference ranges

ALT is a frequently performed blood test, and is a marker of liver cell damage.  However, many patients with liver damage have a normal ALT. So what is a logical approach to setting cut-offs for ALT? And let's get real - we know (because we've studied it) that most clinicians see reference ranges as normal ranges, and so hence results outside reference ranges are seen as abnormal.

As a clinician, given that we know that a "normal" ALT does not rule out liver disease, what we probably want to know is "what level of ALT is clearly abnormal and needs explanation?" (with the knowledge that for a patient with risk factors for liver disease we will not be relying on liver transaminases as a screening test).

Here's the cumulative frequency graph for ALT for all specimens from primary care for men and women. I have ignored all results above 100 - which is about 10% of all results. This moves into results that are much more likely to come from patients with pathology. So this graph then represents a reasonably "normal" distribution of ALT in our population, with the caveat that obesity rates run at about 25%. 

Looking at different cut off values, we can estimate the percentage of a normal population that would be above this value.

ALT cut off = 35  leads to 13% of women and 18% of men with abnormal result

                    = 40                11% of women and 14% of men

                    = 50                  7% of women and 10% of men

                    = 60                  4% of women and  6% of men

                    = 80                  2% of women and  2% of men

What is the uncertainty of measurement? We can look at people with relatively normal ALTs (12-50) and see what the value was if was repeated on the same day. This can be plotted as a cumulative frequency graph and we can see that we can have about 90% certainty that a result will lie somewhere between +/- 20% of the initial value.

This fits well with the published data (Westgard) which suggests a CVi of 20.

There are some implications of this for clinical interpretation and quality control.

1. We probably shouldn't worry about ALTs until they get to about 80.

2. We need to make sure that our laboratory quality control, which focusses purely on technical precision and accuracy, reflects this much larger total uncertainty in the result. Again the Westgard site is helpful, suggesting we need to make sure that precision is within 9.7%; inaccuracy within 11.5%; and total error within 27%. 

We do not need to be that accurate in measuring ALT - it just does not have the clinical imperative that we might see for things such as potassium and creatinine. I want clinical results that reflect this.

As an aside, here's a graph of ALT distributions across the years, and it is easy to spot the analyser change in 2018. I do not understand why this problem cannot be sorted out by standardisation to common reference material; or just through EQA schemes. This just creates confusion and seems both overly scientific in a failure to accept clinical reality; and under-scientific in that it clearly does not relate the measurement to a stable gold standard.