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.