I wrote this rejoinder to a paper regarding the insufficient validation of thyroid function assays especially FT4 and FT3. This echoes the talk I gave to TUK at Meriden several years ago. Show things have got no better in the interim.
Global FT4 immunoassay standardization. Response to: Kratzsch J et al. Global FT4 immunoassay standardization: an expert opinion review
February 2021Clinical Chemistry and Laboratory Medicine 59(6) Follow journal
DOI: 10.1515/cclm-2021-0036
This is diogenes' rejoinder (though I can only see the first page):
degruyter.com/document/doi/...
And these are two papers which cite diogenes' paper:
Free-thyroxine standardization: waiting for Godot while well serving our patients today
degruyter.com/document/doi/...
Triiodothyronine alongside levothyroxine in the management of hypothyroidism?
tandfonline.com/doi/full/10...
This is the whole text minus references:
Global FT4 immunoassay standardization. Response to: Kratzsch J et al. Global FT4 immunoassay standardization: an expert opinion review
February 2021 Clinical Chemistry and Laboratory Medicine 59(6)
DOI: 10.1515/cclm-2021-0036
John Edward M MidgleyJ
Article
Global FT4 immunoassay standardization. Response to: Kratzsch J et al. Global FT4 immunoassay standardization: an expert opinion review
Page 1
Global FT4 Immunoassay Standardizatio Even after many years of use, harmonisation of free thyroid hormone assays still appears to be a distant prospect (1). Forty years after the invention and production of the one-step testsfor free thyroxine (FT4) and free triiodothyronine (FT3), in which I had a role as an inventor(2), rationalisation and harmonising of such assays (including the two-step alternatives from different manufacturers) has still not been resolved. Why is this so? I would like to briefly comment on three intertwined obstacles that must be overcome to achieve a successful outcome.A major barrier to progress has been the various later attempts at exploring the basic natureof these assays. All of them misapprehend how the assays work, being either theoretically bogus (3), or practically invalid either from a general mistaken examination by disassemblyof the assay components (3-7). Illegitimate claims result both from such an approach, while in some studies the wrong conditions were used to compare socalled gold standard methods with only a few examples of working assays (8). Such work and many other studies has, by making general conclusions from only examining a small selection of available tests, tarred all with the same brush. This is neither justified nor acceptable.The first problem is the general failure of assay designers to properly understand the complexity of devising and testing these assays for routine use. In the initial phase and trialling of the first such tests, to thoroughly examine the assays’ performance, the development used sera from many classes of individuals This was done not only in the
Page 2
frequently encountered circumstances, such as differentiation of hypo-, eu- and hyperthyroid groups, those on T4 therapy, and in the three trimesters of pregnancy, but additionally,individuals with variations in thyroxine binding protein concentrations (TBG) from zero to four times the mean concentration of the reference range, analbuminemics, familial dysalbuminemic hyperthyroxinemics (FDH), sera with high concentrations of T4 and T3-containing autoantibodies , and various states and forms of nonthyroidal illness (NTI) (9).The tests were additionally supported by comparison with equilibrium dialysis. Correlationsbetween TBG, transthyretin and albumin with FT4 or FT3 were also examined in healthypersons. By such comprehensive testing protocols, appropriate findings in the rare groups consolidated the assays’ accuracy and precision in the more common cases. Rarely, if at all,has any other test since been validated using a similar rigorous examination before submission for licence to market the method. Rather methods were merely copied and justified in commonly encountered patient groups without applying a deeper understanding of the care needed to produce a comprehensively acceptable performance in more challenging situations. The exhaustive protocol of testing used in the first assays uncovered hitherto unknown problems, which were largely corrected in later developments (9,10). Such duty of care was no longer maintained by recent relaxed protocols. Crucially, awareness of the especial difficulties of producing a valid FT3 test appears to be lacking. This requires an order of magnitude of greater understanding of the tests even than for FT4. The apparent success of such imperfect assays in general cases does not validate their performance in rare sera. Modification costs may contribute to an unwillingness to refine existing assays, because the cost of improvement may outweigh the perceived additional financial return.
Page 3
The second failure has been by the regulators who determine the criteria and give permission for the tests to be marketable. The necessary basic validations appropriate for a free analyte assay are far more searching than required for the total hormone tests. Not only should precision and specificity be examined, but also the special requirements for assay validity.These include a) robustness of the assay results to progressive serum dilution, b) acceptable performance in rare categories and c) extraction of analyte by the test’s antibody sufficiently small as to negligibly affect FT4 or FT3 measurement in all categories. Regulatory requirements are instead rooted in the requirements for validation of total hormone assays,which though necessary, are here fundamentally inadequate as a test of validity. The third culpable entity is the lenient reaction and tolerant attitude of the medical disciplineto this unsatisfactory state of affairs. It is surprising that in the intercourse between producerand customer there has been no active demand by the latter for improving accuracy, precision and robustness in the various assays offered. It is usual that if offerings vary so much in aproduct, the customer will demand to have a more consistent performance in all. In the current environment, some financial constraints are likely to unduly influence the selection ofassay groups over performance. The problem is accentuated by the present system of multi-assay offerings in a dedicated system. If within a given platform, methods for FT4 and FT3 are inadequate, it becomes almost impossible to measure these separately by a different system. Such variation in test results causes unnecessary revalidation work if tests are subject to a change in product.
Page 4
In conclusion, for significant progress in rationalisation of tests to occur, regulators themselves needed to strengthen the requirements for valid working assays. This must include robustness to progressive serum dilution and independence from transport protein differences. Only stricter licensing rules will force producers to deliver on the promise of rationalisation and harmonisation of contemporary FT4 and FT3 assays, which is well within their capability and the public interest.
This is probably a really useful document. Unfortunately it is broadly beyond my comprehension! 😂
I think it says that thyroid hormone assays are unreliable and needn't be if the medical establishment was more exacting in its requirements.
Back in 2007, the biochemists of the UK started the Pathology Harmony Group and initiative.
They got as far as launching a website. And posting a page of A4:
acb.org.uk/static/eea82309-...
It is hard to find anything later than 2013.
Whilst this is distinct to diogenes' issues, it is related. You would expect two valid tests to have similar reference intervals. You cannot harmonise reference intervals when dealing with tests that exhibit different behaviours.
The inertia will be difficult to push through. Reputations are built on the current ‘state’. Once those people retire or they ‘drop off the twig’ perhaps new ideas will be allowed to push through the crust and blossom.
The recent flurry of new work challenging some of the old assumptions might be an indicator of a ‘new spring’ of thought as an old winter fades. (I’m feeling analogised 😂).
Honestly though, we all know it’s far easier and cheaper to gaslight patients and send them off with antidepressants. It won’t be just happening in the field of thyroid diseases. Have spoken (just today) with someone who was working in the field of mental health in NHS (now retired). They stated they had people coming through for treatment who had physical issues that needed treatment not mental health and (as many of us know) agreed mental health was too often a symptom of an underlying badly managed health problem.
When financial considerations overtook wellness in the raison d’être of the health care system - they ceased to care. Any positive outcomes now hinge on the wellness happening to concur with the financial. Financial wins out in all other cases.
Such a false economy but great for drug company profits 🙄
Very bad for GDP. Hopefully the establishment will realise- not much good having a sizeable minority of the country parked, inadequately treated, ill and burbling. 🙄
Old ladies, waste of space attitudes very hard to shift it seems, absurd and stupid tho they are.
