Thread by @ColdOneder

About that new SIDS study that people are saying has found the cause: I am sorry to say that it has not.

It has identified an enzyme that MIGHT be potential biomarker for SIDS vulnerability. And even that is a stretch.

I’ll try to explain.

🧵1/

SIDS is devastating and I would be elated if a cause was discovered. This type of research is firmly in my professional wheelhouse. I was thrilled when I saw proclamations that the cause of SIDS had been discovered, and that parents don't have to worry about risk anymore!

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Here is the press article that most people read:
biospace.com/article/resear…

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When I read that press article I knew the claims it was making were not really possible. So I went to the actual study and was disappointed. The study makes logical leaps that aren’t well supported by data. The press article is just irresponsible.

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Here is a second irresponsible press article:

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abc.net.au/news/2022-05-0…

I understand that the lead author of the study lost her own child to SIDS, which is devastating. It makes sense and it is admirable that she would be so devoted to researching the cause.

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While this study has found something that warrants further investigation, the hype on this finding is unwarranted and gives false hope at best. At worst, it will lead parents to think that they can safely abandon safe infant sleeping practices.

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I’ve already seen a ton of tweets about parents relieved that they can let their babies sleep on their tummies. NO, you should not! ALWAYS on the back and on a safe surface!

HealthyChildren.org/SafeSleep

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Now, to the study itself:

doi.org/10.1016/j.ebio…
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The authors are claiming that the enzyme Butyrylcholinesterase (abbreviated BChE) is a potential biomarker for SIDS. Okay, that seems reasonable. They analyzed dried blood samples from newborns for the amount of BChE.

10/

They had 2 main groups of infants. Those that had died from SIDS, and those that had died from non-SIDS causes. For each 1 of the infant deaths, they matched them by age and sex with ~10 infants that are still alive.

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They compared the BChE levels of the infants that had died from SIDS to their matched (living) controls. They similarly compared the BChE levels of the infants that had died from non-SIDS causes to a different group of matched (living) controls.

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The infants that had died from SIDS had lower BChE levels than their controls, while the infants that had died from non-SIDS causes did not differ from controls. That is the finding of the study. So that means they found the cause of SIDS, right? Sadly, NO. Far from it.

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BChE is a type of cholinesterase, which are enzymes that break down the neurotransmitter acetylcholine (abbreviated ACh). The most famous cholinesterase is called acetylcholinesterase (AChE). AChE and BChE are similar enzymes.

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The ACh system is a diffuse neuromodulatory system. It has lots of actions and widespread targets throughout the body. It's most famous for making skeletal muscles contract and for being the communicator for the "rest and digest" arm of the autonomic nervous system.

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The ACh system is also implicated in arousal from sleep. So it can make someone wake up, or have muscle spasms, but could also make them relax, depending on what cells in the body it's acting on? Oh, it can also stop your heart. You can see how this gets complicated.

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The only other two studies of cholinesterases in SIDS showed: 1) no difference in AChE between SIDS and control. 2) HIGHER AChE in SIDS compared to control. That's the opposite of the current study.

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Cholinesterases like BChE and AChE break down ACh, which would decrease ACh amount. So if BChE is decreased, ACh activity should increase (it's more nuanced than this, but oh well).

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So if BChE is low in SIDS, ACh activity would be increased, and we know that high ACh activity causes SIDS, right? We do not. Autonomic dysregulation is suspected, but we don't know exactly in which direction and which arm is to blame ("fight & flight" or "rest & digest").

19/

Plenty of other suspected causes of SIDS. The prevailing model, the "triple-risk hypothesis" is the best idea we have at this point. It involves an infant with an underlying vulnerability, at a certain age, with an environmental stressor. All 3 things converge in SIDS.

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Could the low BChE be the underlying vulnerability? Maybe. I don't think it is, but I'd be thrilled to be wrong! Only future studies will tell. Back to the paper...

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There were only 26 SIDS deaths and 30 non-SIDS deaths represented. That is a small number. Certainly too small to make sweeping claims.

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They omitted 6 patients' results from the non-SIDS death group because their BChE values "fell below the standard curve". Remember, the claim is that values are lower in SIDS deaths. There were no omissions from other groups.

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The effect is small. Here is the main plot. The one that this entire claim hinges on. I've circled the SIDS death group:

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That is a small difference. While their tests showed it was significant, looking at the data puts things in perspective. Is THAT the cause of SIDS? I don't think it is, unfortunately. The variability in the groups is huge. Guess I have to start a new thread now.

25/25

New (continued) thread:
The SIDS BChE study contains mostly speculation. It's okay to speculate a bit in scientific articles, but this paper is primarily speculation.

1/

There are a lot of claims that are not supported by data, and references to solid studies that are only loosely relevant, but connected in kind of a hand-wavey fashion.

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I don't want to get into the details on this thread, but I will quote one passage:
"...it has been suggested that BChE may be involved in maintaining ACh levels in the arousal systems of the central nervous system"

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This passage is followed by a citation to a fairly old paper that doesn't even mention ACh, let alone BChE. Not sure what got screwed up with the references there, but that is a main thing that the paper hinges on.

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I forgot to mention that the SIDS death group is (by definition) no older than 12 mos. They included kids up to 24 mos in the non-SIDS death group, which they do fairly list as a limitation.

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SIDS is a diagnosis of exclusion, with unknown cause (by definition). The underlying causes of SIDS are likely varied, and while there may be commonalities in many cases, there are surely a variety of etiologies.

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My beef isn't really with the paper. It's with the irresponsible press coverage. I don't really want to tweet the quotes, but I'll do a couple just so I can help other people understand that they are not accurate.

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"On Saturday, researchers... released a study that confirmed not only how these infants die, but why"

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"Now that we know that BChE is involved, we can begin to change the outcome for these babies and make SIDS a thing of the past"

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"Hailed as a 'game-changer' to 'every parent's worst nightmare', the discovery of BChE also provides answers to parents... whose healthy babies died 'on their watch'... "These families can now live with the knowledge that this was not their fault'.

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That is devastating. The deaths, the feelings of guilt. The promise that this absolves people. It is NOT any parent's fault when a baby dies from SIDS. I agree! But it is not because of this study.

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All we do know is that SIDS rates dropped a LOT with safe sleeping campaigns. That is just as important now as it was before this study came out. And we need to keep promoting safe infant sleep. But some babies will still succumb to SIDS, despite any measures.

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This is why researchers (like the study authors!) are working diligently on investigations into SIDS. There is a very logical follow-up study, and I think it should be prioritized:

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There are gene variants that cause BChE deficiencies. BChE deficiency is mostly benign, but can be quite troublesome when certain drugs are given during anesthesia. We can do genetic tests for BChE variants in SIDS. That should give us some good info.

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SIDS is not the fault of the parents, no matter what this study says or doesn't say. That hasn't changed. Please, follow safe infant sleeping practices to ensure that any risk is minimized. The challenge is to also rest easy that you are a good parent!

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I know how hard it is to rest easy. I woke up in a panic every night for 4 months with my first baby, thinking he was suffocating. I would vault out of bed to check on him and find him sleeping soundly in his crib.

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All we can do is all we can do. And I hope to see press releases with some great news about SIDS research in the future! While this lead has been overblown by the press, I hope it turns into something promising. Always grateful to all the researchers!

17/17

Linking this helpful thread that I just noticed from an MD.

https://twitter.com/JonMarronMD/status/1524888237256241153?s=20&t=MmjwyOu2CJlfIDATBmdm8Q

Ugh, my link to the study was broken. Here's one that should work:

sciencedirect.com/science/articl…

I want to reiterate: SIDS deaths are NOT the caregivers' fault! That was true before this study, and this study changes nothing in that respect. We do NOT know what causes SIDS. Parents should not be made to feel guilty after the worst thing possible has happened to them.

There are some more statements from the lead study author in another press article. I’m not going to link to it because it’s from the Da*ly Ma*l but you can go see it there if you want. A quote from the article:

"The next stage will be to make measuring levels of this enzyme a part of routine health checks of newborns. The team will also look at ways to boost the enzyme in babies. She said this process will take about five years but added further research is required."

I’m not sure if the study author's words were misrepresented, but this is not a very realistic clinical plan, including the 5-year timeline. A LOT of confirming research would be necessary even before routine BChE screening would be warranted.

The part about boosting the enzyme in babies is incredibly premature. They can try to alter the enzyme in animals but attempting that in infants is just not going to happen. The next steps are replicating the current results and doing BChE genetic tests.

Even those results would be merely correlative. If those pan out, then we'd have to demonstrate a causal link of BChE deficiency -> SIDS. Only then could we even contemplate trying to alter BChE levels. This type of work is crucial and does not move fast.

I will be surprised if this pans out. I would love to be wrong, but I do not think the finding will hold up in follow-up studies. I am not being mean, I am just thinking like a scientist. Only the data will tell. I hope we get some answers that help explain the tragedy of SIDS.

In an interview, the lead author emphasized the importance of following safe sleep guidelines. I should note that her research is crowd-funded. She also made some other statements:
spreaker.com/user/nzme/dr-c…

“I actually want to give hope to those people, and... it’s not tomorrow that I can give this to you, but I KNOW [emphasis mine] that in 3 to 5 years’ time, SIDS will be a thing of the past.”

“But to get us there, we need a lot of funding, so you know, and that’s as quick as we can get the funding, run the tests, run the, you know, appropriate interventions in trials, then the quicker we’ll be able to give you an answer...”