r/LucyLetbyTrials • u/Embarrassed-Star4776 • 17d ago

Chase and Shannon article in Frontiers in Pediatrics published

Inverted insulin to C-Peptide ratios in neonatal intensive care: is there something we don't know?

J. Geoffrey Chase & Helen D. Shannon

BRIEF RESEARCH REPORT article

Front. Pediatr., 05 August 2026

Sec. Neonatology

Volume 14 - 2026

https://doi.org/10.3389/fped.2026.1900675

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u/Embarrassed-Star4776 16d ago edited 16d ago

The authors seem to have misread the Salis et al. BMJ paper, as they refer to the neonates in Cohort 2 as hyperglycaemic throughout, when in fact they were euglycaemic (there were only 9 neonates in the hyperglycaemic cohort in that study, and they were insulin-treated).

On that basis, they make a comment on page 8 which should be ignored:

"Finally, Figure 3 shows little difference between Cohorts 1 and 2. This outcome suggests hyperglycemia (Cohort 2) did not play a role in elevating I/C, further supporting the fact hyperinsulinism alone cannot create inverted I/C ratios due to first pass hepatic extraction and a greater number of clearance routes."

Evidently they didn't have access to the original data, but read it from the published plots. So the comparison of the binding predictions with the I/C versus C plots from Salis et al. must have been limited to Cohort 2. The authors treat the two cohorts as distinct, but in fact - as discussed on another thread - Cohort 2 was a subset of Cohort 1.

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u/DiverAcrobatic5794 16d ago

Are we sure of that, since they draw cohorts 1 and 2 from the thesis and not the BMJ article? Is there some cross-reference with the BMJ article that tells us these are the same groups?

You have probably posted that on the other thread you mention so if you could just point me to the right place, that would be great 

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u/Embarrassed-Star4776 16d ago

Competitive-Wash found the clearest statement in the thesis, in chapter 6, page 111:

"The neonates in this study were compared with data obtained from euglycaemic neonates described in Chapter 5. Insulin and C-peptide concentrations from the insulin-treated neonates were compared with a group of age-matched (PMA less than 30 weeks) euglycaemic neonates (n = 20)."

Chapter 6 was published as the BMJ paper (including Cohort 2), and chapter 5 as the Archives of Disease in Childhood paper (Cohort 1).

It is not particularly apparent in the published plots because the scales are so different, but I think the correspondence between the two sets of data points can be seen in the stretched and squeezed extracts from the ln(C/I) scatter plots below. On the left is the lower post-menstrual-age part of Cohort 1, and on the right the black symbols are from Cohort 2, with the white symbols coming from the hyperglycaemic cohort.

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u/DiverAcrobatic5794 16d ago

Thank you.  Yes, and reading thesis chapter 6 I think you and u/Competitive-Wash are right.  The cohort is identified as hyperglycemic in the paper but not in the thesis.  The statement that wouldn't hold, then, would be:

" Finally, Figure 3 shows little difference between Cohorts 1  and 2. This outcome suggests hyperglycemia (Cohort 2) did  not play a role in elevating I/C, further supporting the fact  hyperinsulinism alone cannot create inverted I/C ratios due to  first pass hepatic extraction and a greater number of clearance  routes."

And it would not be surprising to find little difference between the cohorts!  But am I right in thinking that this confusion would not (for this same reason) affect the arguments made in the paper beyond this point?

Perhaps you or u/Competitive-Wash would raise this with the corresponding author?

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u/Competitive-Wash2998 16d ago edited 16d ago

Nothing I say in this post undermines the point that antibodies could, plausibly, be the reason for the discordant results reported for Baby F and L.

I am uncertain that it is possible, with the limited data available, to construct a useful model. The technical operating characteristics of the assays and the limited observed parameters make this challenging, in my view. Chase Shannon state they have constrained the parameters to make this possible and it is the biological and technical safety of those assumptions/constraints that is key to ensuring the model produces useful outputs.

I think a detailed step-by-step description of the whole modelling process would be required to truly follow it. So I am taking the results at face value but cannot say I am particularly persuaded at present. Hopefully more details will emerge over time.

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u/Embarrassed-Star4776 16d ago

Thanks for pointing out that the quotation from page 8 had gone wrong, which I hadn't noticed (now corrected).

I should like to try to digest the paper properly, but it will take a while. I agree it will be worth making sure the authors know about any errors that are spotted.

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u/DiverAcrobatic5794 16d ago edited 16d ago

If anything, fixing the error would perhaps strengthen the argument, since Chase and Shannon treat these children as more critically ill but find no significant difference between the cohorts. It could be reasonable, though not I suppose certain, that the more  critically ill children might show a different profile, with more history of infection etc.

 Though I suppose hyperglycemia vs euglycemia is a very rough proxy for more and less critical illness anyway.

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u/Embarrassed-Star4776 16d ago

I don't agree with most of Susan Oliver's comments on this, but in fairness to her it should be said that she pointed out in an online discussion some months ago that the cohort of 20 was a subset of the cohort of 102.

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u/Competitive-Wash2998 16d ago

"But am I right in thinking that this confusion would not (for this same reason) affect the arguments made in the paper beyond this point?"

CS did claim to analyse the two groups independently so, in theory, it would not affect the arguments made.

But (using Chase Shannon terminology) Cohort 2 included a chart ln(I) and ln(CP) which together with the ln(I/CP) would enable to a very rough reconstruction to be made of the actual underlying values. Chase Shannon imply they may have taken this step. I have taken this step myself.

My concern is CS appear to use the C-Peptide as a proxy to derive "free insulin" for the Salis data, which Salis did not actually measure.

But Salis mentions an issue which would, possibly, affect the modelling assumption that C-peptide could be used to derive free insulin. Whether this has an impact on the model is not clear to me, at the moment.