Advanced Maternal Age Associated with AIS?

[Dingo]

hdugger

Hey, you're already right. Without your steady persistence, I don't think we would have pursued exercise as strongly as we did. With that, my son has managed to reduce his discomfort to nothing, substantially improve his appearance, and hold his curve steady (or even reduce it by a few degrees). It's made a tremendous difference for his college years, which was really all we ever asked.

That's amazing news!!! If my endless posts helped even one kid they're worth it! Ya know on the surface it sounds crazy but I wouldn't be surprised if over the next few decades scientists develop a safe way to reconcile adult curves. They can straighten adult teeth.... why not the spine? Somebody is probably working on it right now. I am very happy for your son.

[skevimc]

I sort of understand the people with the correct "genetic storm" who don't end up having scoliosis. I'm more unclear about people who don't have the genetic predisposition and yet still are diagnosed with scoliosis, even if they don't progress to surgery.

Is the idea that a smallish curve is unrelated to genetics, and that only larger curves are genetically based? Or are even those in the low risk group genetically different from the general population? That is, is there some hypothetical score below "0" which "normal" people have?

I have a lot of these same questions. And I would imagine many of the scinetists and clinicians do as well. I'm definitely interested in the range of scores of people who progressed but not >40°. Do the scores correlate with curve size at all? I'd imagine that since they didn't present any data on that, that it doesn't really fit the curve very well. OR... I think they could have omitted that data because they didn't have the power to predict that and didn't want people over-reaching or over-interpreting their results/score.

Based on their results, the larger curves certainly seem to be heavily influenced by genetics. But OTOH, a high score doesn't guarantee you will have surgery. I'd also imagine that the normal/non-scoliotic population would have scores from 0 up to at least 150 or so. But that's purely a guess based on nothing more than human variability.

One thing I've wondered about the Scoliscore test is whether the low risk group are simply less likely to progress, or whether they're people in whom bracing is more effective. Conversely, are the high risk group people who just tend to progress, or are they people for whom bracing is ineffective.

This is the next question/direction I see opening up. I know it seems like the community over-looks curves <40° as well as adults with curves. And to an extent this has been true. But there are still a lot of people looking at these groups, and actually I think the scoliscore will help to better identify them through the process of elimination.

[Dingo]

Scoliscore could answer two questions I have.

A) Do some of the "curve progression genes" that Scoliscore detects relate to physical size and strength? At least one study found that larger, more muscular individuals have less risk of curve progression.
Relation between adolescent idiopathic scoliosis and morphologic somatotypes.

B) Does the incidence of "curve progression genes" among children with Scoliosis differ from the healthy population? Many studies suggest that there are kids that posess a high risk of Scoliosis but don't have it. The largest twin study ever conducted found that identical twins were typically not concordant for Scoliosis.
Adolescent idiopathic scoliosis in twins: a population-based survey.
High-class athletetic twins discordant for adolescent idiopathic scoliosis.

[rohrer01]

I'm still thinking about the question I posed to Dingo. Obviously I was not thinking and his son is not a candidate for Scoliscore due to him being JIS and not AIS. I'm wondering though how do they know how many cases of AIS are really JIS and would this affect the accuracy of the Scoliscore screening? I'm wondering about this because, at least in my case I started getting "backaches" at around 8 years of age. I was in outright pain by age 12 and could feel the deformity. I wasn't diagnosed until age 16 and was diagnosed with AIS. Hmmmmm.... Does anyone know if they will be doing or have done any studies like this one with JIS people?

[Ballet Mom]

I'm still thinking about the question I posed to Dingo. Obviously I was not thinking and his son is not a candidate for Scoliscore due to him being JIS and not AIS. I'm wondering though how do they know how many cases of AIS are really JIS and would this affect the accuracy of the Scoliscore screening? I'm wondering about this because, at least in my case I started getting "backaches" at around 8 years of age. I was in outright pain by age 12 and could feel the deformity. I wasn't diagnosed until age 16 and was diagnosed with AIS. Hmmmmm.... Does anyone know if they will be doing or have done any studies like this one with JIS people?

Didn't you say you were part of the study that created the Scoliscore? I believe the scientists who developed the Scoliscore believe that juvenile scoliosis is genetically different from AIS.

If the scientists can't tell the difference between the different types of scoliosis, and didn't even ask questions to try and determine whether someone diagnosed with AIS was actually a juvenile case in putting together the genetic data, it certainly calls into question the validity of this test and could certainly explain why it is not accurate.

I have read somewhere that Axial Biotech is trying to make the Scoliscore test available to the juvenile market. I don't know if that means they have to do separate gene testing and it would be a different test from the original Scoliscore.

It actually makes me wonder whether or not the one percent of AIS cases they've identified as not being effective with any type of treatment is actually some other form of scoliosis such as juvenile, which seems to have a much more determined progression towards surgical levels.

[rohrer01]

Yes, I was part of the study. I can't say for sure, and I guess neither can anyone else whether I have AIS or JIS. However, I didn't notice a deformity in myself until I was 12, but that doesn't mean it wasn't there. Yes, I agree with you that this would be a flaw in the study. I don't see how it is even possible to separate the AIS from the JIS patients due to the fact that many of us aren't diagnosed at the age of onset.

[scolio1964]

My daughter's doctor thinks that scoliosis is genetic. I have it and both of my kids do, too. I have many other family members who have it as well.

My daughter was diagnosed at age 7, but I didn't progress enough to wear a brace until she was 11. I noticed her scoliosis at age 7, but her pediatrician did not notice it. I had to show her. I think that if I hadn't had scoliosis myself, that I wouldn't have known to watch for it in her. So, even though she is considered to be JIS, I think that it's only because I found it myself. I bet there are a lot more kids who actually would be considered to have JIS, it just wasn't found earlier.

[Ballet Mom]

Yes, I was part of the study. I can't say for sure, and I guess neither can anyone else whether I have AIS or JIS. However, I didn't notice a deformity in myself until I was 12, but that doesn't mean it wasn't there. Yes, I agree with you that this would be a flaw in the study. I don't see how it is even possible to separate the AIS from the JIS patients due to the fact that many of us aren't diagnosed at the age of onset.

Well, if AIS is genetically different from JIS, Axial Biotech should be able to tell us, lol.

[Ballet Mom]

My daughter's doctor thinks that scoliosis is genetic. I have it and both of my kids do, too. I have many other family members who have it as well.

My daughter was diagnosed at age 7, but I didn't progress enough to wear a brace until she was 11. I noticed her scoliosis at age 7, but her pediatrician did not notice it. I had to show her. I think that if I hadn't had scoliosis myself, that I wouldn't have known to watch for it in her. So, even though she is considered to be JIS, I think that it's only because I found it myself. I bet there are a lot more kids who actually would be considered to have JIS, it just wasn't found earlier.

You have the familial type of scoliosis, which I guess most people other than Dingo thinks is definitely genetic. I actually hope Dingo is right and it turns out to be a disease that can be prevented with a simple vaccination! :-)

My daughter has a sister of a great-grandfather who had quite severe scoliosis apparently. This is the side of the family tree that has the double-jointed joints. But no one else in the extended family has any sign of scoliosis. On my husband's side, there is one case of scoliosis, but also very distant.

It just seems to me, they may be narrowing down to the familial cases, but this may not have any ability to determine anything about the multi-factorial cases, and as such, shouldn't be being used to determine whether they are being braced or not.

[skevimc]

Scoliscore could answer two questions I have.

A) Do some of the "curve progression genes" that Scoliscore detects relate to physical size and strength? At least one study found that larger, more muscular individuals have less risk of curve progression.

This is the thing I'm most interested in. Certainly any muscle specific genes. I'm sure people have already begun looking at what these genes are and no doubt grants and projects are already being written or planned.

B) Does the incidence of "curve progression genes" among children with Scoliosis differ from the healthy population? Many studies suggest that there are kids that posess a high risk of Scoliosis but don't have it. The largest twin study ever conducted found that identical twins were typically not concordant for Scoliosis.

Undoubtedly there would be non-scoliotic people with a relatively higher scoliscore. This is the main reason why it's not, and should not be, a screening tool. The authors make sure to explicitly say this in their discussion.

This panel was designed to provide prognostic information in patients who already have mild scoliosis. This AIS-PT is not applicable as a screening test for the general population because (1) the rate of severe scoliosis is many times lower in the general population than it is in children who already have been diagnosed with mild AIS and (2) many unaffected patients may have the genetic factors favoring curve progression but lack the genetic/environmental factors necessary for initial onset of AIS. Parents of AIS patients often inquire about risks for the younger siblings of their AIS affected children. However, these questions have been difficult to answer with any reliability, and this AIS-PT is not designed to predict risk for siblings of affected patients either.

AIS-PT = AIS Prognostic Test

The twin studies actually fit this study really well. The general population measured in the large study showed a 25% concordance for monozygotic (identical) and 0 concordance for dizygotic (fraternal). So there's clear evidence that genetics and environment play a pivotal role. In earlier studies, the concordance rate was higher, ~70-90%, and this was thought to be because the data was taken from clinics and thus, would favor identical twins both having AIS and probably more in the moderate to severe range. Since the scoliscore measures the progression risk, and those who progress to severe curves have a high genetic propensity to progress, it would make sense that more sets of identical twins would both have progressing AIS.

AIS-PT (scoliscore) twin study. The new 'Holy Grail' in AIS research.

I'm still thinking about the question I posed to Dingo. Obviously I was not thinking and his son is not a candidate for Scoliscore due to him being JIS and not AIS. I'm wondering though how do they know how many cases of AIS are really JIS and would this affect the accuracy of the Scoliscore screening? I'm wondering about this because, at least in my case I started getting "backaches" at around 8 years of age. I was in outright pain by age 12 and could feel the deformity. I wasn't diagnosed until age 16 and was diagnosed with AIS. Hmmmmm.... Does anyone know if they will be doing or have done any studies like this one with JIS people?

From the article.

We chose to include 9-year-old, mild scoliosis patients in the AIS cohort because the age of puberty, the point at which AIS is usually detected, has been decreasing since the original age ranges were proposed decades ago.

I think also this captures many of the patients, perhaps like you, that began to develop scoliosis while on the cusp of adolescence.

However, they also caution using the test in the 9 year old mild curve population for the reason you mention above. They make the basic assumption that JIS and AIS have differing genetic markers. Time will tell if they are correct. But for now, that is the statement and assumption.

Don't know if any studies are underway. But if I know researchers, and I do, there are definitely plans underway and/or at least further combing of the existing data set.

[skevimc]

It actually makes me wonder whether or not the one percent of AIS cases they've identified as not being effective with any type of treatment is actually some other form of scoliosis such as juvenile, which seems to have a much more determined progression towards surgical levels.

That's a really good thought. It could also potentially explain the 1% with a low scoliscore but still progressed to surgical range.

[Pooka1]

The twin studies actually fit this study really well. The general population measured in the large study showed a 25% concordance for monozygotic (identical) and 0 concordance for dizygotic (fraternal). So there's clear evidence that genetics and environment play a pivotal role. In earlier studies, the concordance rate was higher, ~70-90%, and this was thought to be because the data was taken from clinics and thus, would favor identical twins both having AIS and probably more in the moderate to severe range. Since the scoliscore measures the progression risk, and those who progress to severe curves have a high genetic propensity to progress, it would make sense that more sets of identical twins would both have progressing AIS.

I have seen reserchers dismiss that Danish Twin study on the basis of self-reporting which is notoriously bad for both type of twinning and presence of scoliosis. It's obviously GIGO not just from that standpoint but also from the very low total prevalence (incidence?) of scoliosis in that large group of people compared to the actual rate in the population. The other studies that verify both type of twinning and scoliosis clinically all come in at much higher rates.

The best estimate of concordance between monozygotic twins is ~75% and that between fraternal (= any sibling-sibling pair) ~33%. These numbers are in keeping with a strongly genetic etiology which is separately/independently surmised as I understand it. The fact that the identicals are not 100% seems related to epigenetics wherein identical twins have been shown to have wildly different gene copy numbers for instance. I think if they can link copy number to the genes identified in Scoliscore they may be onto something.

Then there is Ogilvie who has stated that twin studies are not applicable to scoliosis study because, as a midline disorder, you shouldn't be looking a splitting zygotes per se. I think he has a point. That issue may explain why the concordance is only ~75% and not 100% between monzygotic twinning alone and all by itself.

And last, the people who are desperately hoping for a straight germ theory of scoliosis better hope it doesn't turn out to be a retrovirus like HIV which continues to defy development of an effective vaccine. Careful what you wish for...

[skevimc]

I have seen reserchers dismiss that Danish Twin study on the basis of self-reporting which is notoriously bad for both type of twinning and presence of scoliosis. It's obviously GIGO not just from that standpoint but also from the very low total prevalence (incidence?) of scoliosis in that large group of people compared to the actual rate in the population. The other studies that verify both type of twinning and scoliosis clinically all come in at much higher rates.

Are the researchers who dismiss the study completely dismissing it?

The clinical rate would also be flawed because these are scoliosis practices, i.e. only seeing those cases that need following.

The best estimate of concordance between monozygotic twins is ~75% and that between fraternal (= any sibling-sibling pair) ~33%. These numbers are in keeping with a strongly genetic etiology which is separately/independently surmised as I understand it.

For clinically measured concordance, I don't doubt these numbers at all. Patients seen clinically will more than likely be the more progressive and potentially severe cases. So the genetic cause for progression would be strong in these twins. So if you have one twin who would have a high scoliscore, the other twin would as well, and so both would be seen in the clinic.

I don't see any of the twin studies being contradictory.

[Pooka1]

Are the researchers who dismiss the study completely dismissing it?

The articles I have read have the authors going with the ~75% or better even when they mention the Danish study. I have posted some of these articles on the forum.

The clinical rate would also be flawed because these are scoliosis practices, i.e. only seeing those cases that need following.

But that is the reason the self-reporting is flawed. Many people have scoliosis (Cobb > 10*) and never know it. It is clearly GIGO.

For clinically measured concordance, I don't doubt these numbers at all. Patients seen clinically will more than likely be the more progressive and potentially severe cases. So the genetic cause for progression would be strong in these twins. So if you have one twin who would have a high scoliscore, the other twin would as well, and so both would be seen in the clinic.

I don't see any of the twin studies being contradictory.

I believe I can convince you they are contradictory. Consider this article:

http://www.ncbi.nlm.nih.gov/pubmed/9306532

RESULTS: Thirty-seven sets of twins were monozygous, and 31 sets were dizygous.

So all these twins presumably have severe scoliosis because they are in the clinic per your suggestion. And yet the ratio of monozygotic to dizogotic is greater than one when out in the general population the "natural" ratio before IVF was ~0.3 and would only go DOWN from there in response to IVF. And yet it is greater than one among the patients here.

It's a small patient population but this is actually more proof beyond the GIGO argument (which is the strongest argument by far) because the ratio of these test subjects is way off what would be expected by their presence in the general population.

[rohrer01]

How do they define concordance in mz twins? Do they both have to be affected and that's all, or do they have to share the same curve pattern/severity as well? I know some strange things can happen in mz twinning, but, at least in females you have to consider X-inactivation. If any part of the combination of genes that contribute to the scoliosis is carried on the X chromosome, that could account for the <100% concordance in females, correct? However, straight X-linked diseases would primarily affect males (as was not made clear in my statement about my family hx). Does anyone know if they separate the males from the females in conducting mz twin studies? I think that could be useful information.