HbA1c – use the right model, please

August 31, 2017

I had occasion to read a paper (CCLM paper) about HbA1c goals and evaluation results. This paper refers to an earlier paper (CC paper) which says that Sigma Metrics should be used for HbA1c.

So here are some problems with all of this.

The CC paper says that TAE (which they use) is derived from bias and imprecision. Now I have many blog entries as well as peer reviewed publications going back to 1991 saying that this approach is flawed. That the authors chose to ignore this prior work doesn’t mean the prior work doesn’t exist – it does – or that it is somehow not relevant – it is.

In the CC paper, controls were used to arrive at conclusions. But real data involves patient samples so the conclusions are not necessarily transferable. And in the CCLM paper, patient samples are used without any mention as to whether the CC paper conclusions still apply.

In the CCLM paper, precision studies, a method comparison, linearity, and interferences were carried out. This is hard to understand since the TAE model of (absolute) average bias + 2x imprecision does not account for either linearity or interference studies.

The linearity study says it followed CLSI EP6 but there are no results to show this (e.g., no reported higher order polynomial regressions). The graphs shown, do look linear.

But the interference studies are more troubling. From what I can make of it, the target values are given ± 10% bands and any candidate interfering substance whose data does not fall outside of these bands is said to not clinically interfere (e.g., the bias is less than absolute 10%). But that does not mean there is no bias! To see how silly this is, one could say if the average bias from regression was less than absolute 10%, it should be set to zero since there was no clinical interference.

The real problem is that the authors’ chosen TAE model cannot account for interferences – such biases are not in their model. But interference biases still contribute to TAE! And what do the reported values of six sigma mean? They are valid only for samples containing no interfering substances. That’s neither practical nor meaningful.

Now one could better model things by adding an interference term to TAE and simulating various patient populations as a function of interfering substances (including the occurrence of multiple interfering substances). But Sigma Metrics, to my knowledge cannot do this.

Another comment is that whereas HbA1c is not glucose, the subject matter is diabetes and in the glucose meter world, error grids are well known as a way to evaluate required clinical performance. But the term “error grid” does not appear in either paper.

Error grids account for the entire range of the assay. It seems that Sigma Metrics are chosen to apply at only one point in the assay.

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Allowable limit for blood lead – why does it keep changing

August 19, 2017

A recent article suggests the CDC limit for blood lead may be lowered again. The logic for this is to base the limit on the 97.5th percentile of NHANES data, and to revisit the limit every 4 years. An article in Pediatrics has the details. Basically, the 97.5th percentile for blood lead has been decreasing – it was around 7 in 2000. And in the Pediatrics article it is stated that: “No safe blood lead concentration in children has been identified.” Nor has human physiology changed!

It’s hard to understand the logic behind the limit. If a child had a blood lead of 6 in 2011, the child was ok according to the CDC standard, but not ok in 2013. Similarly, a blood lead of 4 in 2016 was ok but not in 2017?

Here is a summary of lead standards in the USA through time.

1960s 60ug/dL
1978   30ug/dL
1985   25ug/dL
1991   10 ug/dL
2012    5 ug/dL
2017?   3.48 ug/dL


The difference between reviewing an article and writing a commentary about it

August 13, 2017

Recently, I was asked to review an article, which I did. I thought the article was impressive but as usual I still recommended some ways to improve it. Upon resubmission, I reviewed it again – my recommendations were implemented – and the article was published (online first). But that’s not the end of the story. A while later I was asked to write a commentary about the article, which would be published along with the article.

In a sense, I had to review it again and this time was more critical. It was (and is) an impressive article but when my commentary is published, I have to be sure that I have written about all of the positive parts of the article and any remaining deficiencies. Hence I found new deficiencies!

It reminds me when I managed a group at Ciba Corning that I always insisted on a written rather than a verbal report. A verbal report is ephemeral but when you put your name on something you think about it much deeper.

 


Reviewing an article without commenting

July 26, 2017

I recently reviewed a paper for a journal and my recommendation was “accept with minor modifications”, whereby my suggestions for improvement were provided to the authors – as is usual. Eventually, the paper was resubmitted – my suggestions were implemented and I recommended “accept.” But I noticed that the other reviewer had recommended reject with no comments to the authors other than saying it was an article of limited interest. As a sometimes author I would have been pretty unhappy with such sparse feedback. I think authors deserve better.


Being invited to submit articles

July 26, 2017

These requests are not coming from Clinical Chemistry or similar journals. In the last two weeks, here is a list of journals requesting me to submit an article. Many (all?) require fees to publish your article.

Journal of Clinical Research and Ophthalmology
Open Access Journal of Diabetes
Endocrinological diabetes Clinical and Medical Research
Archives of Preventive Medicine
International Journal of Diabetes and Clinical Research

EC Diabetes and Metabolic Research
Journal of International Medical Research
European Journal of Biomedical and Pharmaceutical Sciences
Functional Foods in Health and Disease Journal
International Journal of Engineering Inventions
Analytical Electrochemistry
Journal of Palliative Care
Advances in Mechanical Engineering
Diabetes Management
Journal Cell Biology & Cell Metabolism
International Journal of Sports and Exercise Medicine
Therapeutic Advances in Endocrinology and Metabolism
International Journal of Computational Engneering Research
Journal of Research in Diabetes & Metabolism

 


Limited release for sale

July 12, 2017

When I was in industry, we would have a “release for sale” meeting in order to determine whether the product should be released or not. The person from regulatory affairs was always irksome because he always insisted the product was not ready for release. Yet, two hours or so later he signed the release for sale form. I think he behaved this way to show that 1) he was not some guy who would rubber stamp anything that was put in front of him and 2) if there were product problems he could say, he never wanted to release the product. But he nevertheless always looked bad because basically no new data had been put in front of him, yet he signed the release for sale form without someone putting a gun to his head. If he truly believed the product was not ready, he should have stuck to his guns.

But back to the title…, as a “concession” the marketing guy would say, ok let’s have a limited release for sale implying that fewer units would be delivered than possible. Of course, this was fiction – what the limited release really meant was marketing was limited to selling units as fast as they could, and because of startup issues, product sales usually took some time to get going.

On a more positive note, our release for sale meetings – as I recall – were always unanimous, and not every time was the decision to release – sometimes it was decided to not release the product.


The concept of nano vacations

July 11, 2017

People go on vacation typically for a week or more. A mini vacation is perhaps two days. With our plane, we have been taking nano vacations. For example, the last one was leaving around 10 am, flying to Martha’s Vineyard, walking around Edgartown and having lunch, flying back, and home around 2:30.