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Thread: Advanced Maternal Age Associated with AIS?

  1. #31
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    am wondering how much poorer countries suffer with scoli in terms of lack of sufficient pre natal and post natal care, lack of early diagnosis, etc...
    also...diets low in calcium and other vital nutrients...how much is that contributing to the bigger numbers of scoliosis patients in countries that have a lot of poverty....?
    environmental toxins...? seems like they might be greater in poorer countries...?

    so how do those numbers concerning higher socio economic parents figure in?
    how does the effect of poverty compare to the statistics supposedly there for higher socio economic...and probably also older.... parents...?
    which has more impact in terms of kids having scoli...more money plus older parents, or poorer parents with less money?

    how can all the factors be teased out to know if age is the culprit?

    jess

  2. #32
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    Quote Originally Posted by jrnyc View Post
    am wondering how much poorer countries suffer with scoli in terms of lack of sufficient pre natal and post natal care, lack of early diagnosis, etc...
    also...diets low in calcium and other vital nutrients...how much is that contributing to the bigger numbers of scoliosis patients in countries that have a lot of poverty....?
    environmental toxins...? seems like they might be greater in poorer countries...?

    so how do those numbers concerning higher socio economic parents figure in?
    how does the effect of poverty compare to the statistics supposedly there for higher socio economic...and probably also older.... parents...?
    which has more impact in terms of kids having scoli...more money plus older parents, or poorer parents with less money?

    how can all the factors be teased out to know if age is the culprit?

    jess
    Exactly. There are known unknowns and unknown unknowns. This type of study seems especially ripe for be false because of this.

    There is a scientific answer but it may be we can never know it. To use an example from Sam Harris, there is one right number for birds in flight worldwide at any given second but we will never be able to determine it. I am not saying maternal age and AIS is quite that refractory but I am saying it might be more refractory than we can know.
    Sharon, mother of identical twin girls with scoliosis

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  3. #33
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    Plus AIS is known to be genetic. How it is inherited is the unknown.
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

    Question: What do you call alternative medicine that works?
    Answer: Medicine


    "We are all African."

  4. #34
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    Researchers in the field accept that idiopathic scoliosis has a genetic component. That genetics is involved is a given at this point. I haven't come across an instance of a scoliosis researcher who says there is some chance genetics is not involved.

    Here is a typical treatment of the acceptance as fact of genetics as a factor in idiopathic scoliosis that can be found in the literature... (emphasis added)

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674301/

    Understanding Genetic Factors in Idiopathic Scoliosis, a Complex Disease of Childhood
    Carol A Wise,1,2,3* Xiaochong Gao,1 Scott Shoemaker,4 Derek Gordon,5 and John A Herring2,6
    1Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX
    2Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX
    3McDermott Center, University of Texas Southwestern Medical Center, Dallas, TX
    4Department of Orthopedics, Kaiser Permanente, San Diego, CA
    5Department of Genetics, Rutgers University, Piscataway, NJ
    6Dept. of Orthopaedic Surgery, Texas Scottish Rite Hospital for Children, Dallas, TX, USA
    *Address correspondence to this author at the Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, 2222 Welborn St, Dallas, TX 75219, USA; Tel: 214-559-7861; Fax: 214-559-7872; E-mail: carol.wise@tsrh.org

    Abstract
    Idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, affecting ~3% of children worldwide. AIS significantly impacts national health in the U. S. alone, creating disfigurement and disability for over 10% of patients and costing billions of dollars annually for treatment. Despite many investigations, the underlying etiology of IS is poorly understood. Twin studies and observations of familial aggregation reveal significant genetic contributions to IS. Several features of the disease including potentially strong genetic effects, the early onset of disease, and standardized diagnostic criteria make IS ideal for genomic approaches to finding risk factors. Here we comprehensively review the genetic contributions to IS and compare those findings to other well-described complex diseases such as Crohn’s disease, type 1 diabetes, psoriasis, and rheumatoid arthritis. We also summarize candidate gene studies and evaluate them in the context of possible disease aetiology. Finally, we provide study designs that apply emerging genomic technologies to this disease. Existing genetic data provide testable hypotheses regarding IS etiology, and also provide proof of principle for applying high-density genome-wide methods to finding susceptibility genes and disease modifiers.

    Is IS genetic?

    The recognition of genetic influences in IS is well-documented [19-25]. Familial forms of IS were described as early as 1922 [26]. Since then, reports of multiple twin sets and twin series have consistently shown higher concordance in monozygotic (MZ) compared to dizygotic (DZ) twins (reviewed in [27]). A meta-analysis of these clinical twin studies revealed 73% MZ compared to 36% DZ concordances [28]. Interestingly, in this series there was a significant correlation with curve severity in monozygous twins (P<.0002), but not dizygous twins. No correlation with curve pattern was found, suggesting the importance of genetic factors in controlling susceptibility and disease course, but not necessarily disease pattern. More recently, Andersen et al. [29] reported their findings using the Danish Twin Registry. They found 25% proband-wise concordance in monozygotic twins (6 of 44 concordant) compared to 0% concordance (0 of 91) in dizygotic twins, with an overall prevalence of approximately 1%. The lower concordances in both groups as compared with prior results may be explained by differences in study design, specifically, ascertainment in clinics versus by registry, and screening by examination versus questionnaire. Nevertheless the overall trend obtained for all studies suggests strong genetic effects in IS. Interestingly, measured concordances in monozygotic twins were below 100%, reflecting the complexity of disease and suggesting the involvement of as yet unknown environmental or stochastic factors in disease susceptibility.

    How is IS Susceptibility Inherited?
    Given that genes contribute to IS, how is disease susceptibility inherited? Autosomal dominant inheritance has been suggested [19-26] from evaluation of single families or small family collections (Fig. (​22)). X-linked dominant inheritance has been a prevailing theory to explain apparent lack of male-male transmission [22]. However this was disputed after re-evaluation of X ray data from original study subjects [23, 27]). Various studies have found that IS disease risk falls off quickly comparing first-degree relatives of a proband to subsequent generations. Other studies found similar trends [23-25]. Specifically, in their comprehensive population study Riseborough et al. reported overall risk to first-degree relatives of 11% compared to 2.4% and 1.4% in second- and third-degree relatives [23]. Interestingly, some but not all studies have found advanced maternal age for mothers of probands with IS [23-25, 30]. These observations may be most consistent with a multifactorial inheritance model involving several to many genes, interplaying with unknown environmental factors. The general consensus gathered from all of this is that, while families with dominant inheritance may exist, IS is generally a “complex” genetic disease that is not easily explained by existing inheritance models.
    Last edited by Pooka1; 01-30-2011 at 09:15 AM.
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

    Question: What do you call alternative medicine that works?
    Answer: Medicine


    "We are all African."

  5. #35
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    Or we can just have another monkey trial...
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

    Question: What do you call alternative medicine that works?
    Answer: Medicine


    "We are all African."

  6. #36
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    jrnyc

    seems like they might be greater in poorer countries...?
    Many diseases hit poor countries at a higher rate than rich countries. But oddly enough the reverse is also true. Sometimes a "dirtier" environment protects us.

    For example: Exposure to Worm Infection in the Womb May Protect Against Eczema, Study Suggests

    The findings support the hypothesis that maternal worms during pregnancy, neonatal life and early breastfeeding, may protect against allergy in infancy and that treatment of these worms during pregnancy increases the risk of allergy.
    Here is another head scratcher...
    Denmark has 'world's highest cancer rates'

    Denmark has the highest cancer rates in the world, with about 326 people out of every 100,000 developing cancer each year, an analysis of World Health Organisation (WHO) statistics suggests.
    And another...
    Wealthy people more likely to get certain types of cancer

    There was a large difference in lung cancer incidence, with about 35 per 100,000 people being diagnosed in high socio-economic areas compared to about 50 in 100,000 in low socio-economic districts.

    For breast cancer, the rate was 106 per 100,000 people in low socio-economic areas compared to about 122 per 100,000 in high socio-economic areas.

    For skin cancer, the rate was 42 per 100,000 people in low socio-economic areas and 52 per 100,000 in high socio-economic areas.

    With prostate cancer, it was 160 per 100,000 in low socio-economic areas compared to 185 per 100,000 in high socio-economic areas, and for cervical cancer, it was 8 per 100,000 in low socio-economic areas and 6 per 100,000 in high socio-economic areas.
    Figuring out what's going on and why is tough, tough tough!
    Last edited by Dingo; 01-30-2011 at 09:26 AM.

  7. #37
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    Although maternal age suggests an environmental trigger it doesn't exclude the possibility that genes could also be involved. On some level genes are probably involved in every human disease.

    For example:
    Genetic Differences That Make Some People Susceptible to Meningitis Revealed in Major New Study

    Genetic differences that make some people susceptible to developing meningococcal meningitis and septicaemia, and others naturally immune, are revealed in a new study of over 6,000 people, published in Nature Genetics.
    Scientists pinpoint flu gene

    An unlucky combination of "vulnerable" genes could explain why some people recover from the flu overnight and others struggle to shake off the virus for weeks.
    The Leprosy Gene

    An international research team, led by Dr. Erwin Schurr and Dr. Thomas Hudson, Scientists at the Research Institute of the McGill University Health Centre, have identified a gene on human chromosome 6 that makes people vulnerable to leprosy. The report will be published in the March 2003 issue of the journal Nature Genetics.

  8. #38
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    Quote Originally Posted by Dingo View Post
    Although maternal age suggests an environmental trigger it doesn't exclude the possibility that genes could also be involved. On some level genes are probably involved in every human disease.
    Yes, exactly. I'm always surprised when there's such fanfare that "we found a gene." Things are related to things, and many things are built into our genes. It's no more interesting, in the general case, then thinking something is related to the environment.

    The question always is *how* is it related. If you don't know that, you don't know anything.

    For example, are the genes related to scoliosis the same ones that are related to joint hypermobility? In that case, saying it's genetic hasn't told us anything new. Likewise, is an environmental trigger something we already knew made bones weaker. Again, that isn't telling us anything new.

    What's interesting is *specific* information on exactly what effect a gene or environmental trigger takes. That's why the maternal age is interesting. It's not something we already knew was related to scoliosis, and it makes us think about related things.

  9. #39
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    hdugger

    The question always is *how* is it related. If you don't know that, you don't know anything.
    Exactly, the mechanism is key.

    For example maybe a gene leads to hypermobility which in turn increases the chance of Scoliosis.

    Or...

    Maybe a gene makes children susceptible to a particular strain of measles that can trigger an autoimmune response that in turn triggers Scoliosis.

    That's a big difference.

    Genes have been found that appear to increase the risk of Schizophrenia. Are these hallucination genes? Maybe Schizophrenia is the natural byproduct of genes that enhance creativity. New evidence says probably not.

    Schizophrenia Susceptibility Genes Directly Implicated in the Life Cycles of Pathogens: Cytomegalovirus, Influenza, Herpes simplex, Rubella, and Toxoplasma gondii

    One thing I look for in health stories is whether a gene causes a disease or merely raises the risk. If it triggers the disease it's a genetic disease. If it raises the risk it's a susceptability gene. The next question is susceptability to what?
    Last edited by Dingo; 01-30-2011 at 12:36 PM.

  10. #40
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    And maybe genes or a variable but specific set of genes DIRECTLY control lateral curvature, curve apex, progression rate, disc wedging, etc. etc. etc. to include EVERYTHING about scoliosis incidence and progression.

    According to that guy who recently listed the top hypotheses, there is no consensus but most of the things he mentions besides straight genetics seem to under genetic control like hormone and enzymatic pathways. So it seems the 6 hypotheses he mentions are:

    1. genetic outright
    2. genetic secondary
    3. genetic secondary
    4. genetic secondary
    5. genetic secondary
    6. environmental influence

    Perhaps that's why he proceeded his comments at his 2009 POSNA talk with the statement, "It's all genetic."

    I think there is a miasma of semantic ignorance... that is, how these terms are in fact defined and used by experts in the field vice how bunnies use them in the bunny warren here.

    Love,
    A bunny
    Last edited by Pooka1; 01-31-2011 at 06:12 AM.
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

    Question: What do you call alternative medicine that works?
    Answer: Medicine


    "We are all African."

  11. #41
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    Also, on the genetic question (and I should really go find the article before I post this, but I read it on paper and that's just too darn hard to find )

    I was reading an article about how bad published medical papers are (I *think* by the same person who Pooka always quotes, but I'm not certain). This was the "go to" person on evaluating medical articles. Anyway, he specifically called out genetic research as being one of the worst areas (along with drug studies.)

    Ah, I've found the article - http://www.theatlantic.com/magazine/...-science/8269/ - but not managed to read all of it.

    Here's the quote about genetic research:

    "The exciting links between genes and various diseases and traits that are relentlessly hyped in the press for heralding miraculous around-the-corner treatments for everything from colon cancer to schizophrenia have in the past proved so vulnerable to error and distortion, Ioannidis has found, that in some cases you’d have done about as well by throwing darts at a chart of the genome."

    As any rationale person would expect, the most flawed areas are the ones where money/fame exert an influence. Thus, those diligent torso rotation authors aren't out for the big bucks and are thus unlikely to be motivated by anything other than curiosity. Research associated with anything that bring in money and/or which is backed by big business, OTOH, is always suspect. It *may* be clean, but it always deserves extra scrutiny. That's just common sense 101.

  12. #42
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    Quote Originally Posted by hdugger View Post
    As any rationale person would expect, the most flawed areas are the ones where money/fame exert an influence. Thus, those diligent torso rotation authors aren't out for the big bucks and are thus unlikely to be motivated by anything other than curiosity.
    And yet Mooney double published all the data from a pub in a second pub without mentioning it. So he had a TOTAL of 20 patients, a fact which is missed by many bunnies. And that of course raises the question of why he is double-publishing few year old data rather than following up with those original patients. And it also might be related to why Mooney avoided some direct questions from other TRS researchers. There has never been a long term study on PT as far as I know and there is DEFINITELY no long term study on torso rotation. There is a total of 35 patients on which there is published data for torso rotation in the world and over the entirety of human history.

    Finally, I thought Mooney was involved in some deal with some gym on this stuff so I don't think we can assume there is no money connection there. But even if there isn't big money, I think the fame and power aspect is just as strong or stronger. For example, there is no other rational explanation for why Bloomberg is a three-term major of NYC, arguably the worse job in the world, rather than laying on a beach in Fiji. None.
    Sharon, mother of identical twin girls with scoliosis

    No island of sanity.

    Question: What do you call alternative medicine that works?
    Answer: Medicine


    "We are all African."

  13. #43
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    My takeaway from all this, and as someone who did medical research, is to treat published articles the same way you'd treat an unknown person posting on the forum. Who are they? Why are they posting this? Why might they want to report this particular result?

    I'm fairly trusting of the stuff I consider "personal communications" between doctors. So, doctors posting on the success of this or that procedure, or complication rates, and so on. That stuff may reach the wrong conclusion, but it's generally clean of ulterior motives. That said, I place more faith in Linda's reports of what she's seen in clinic over any research I've read. There's a way that people pull out the essentials from seeing a large number of cases that is simply better then the way they do research.

  14. #44
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    hdugger

    Anyway, he specifically called out genetic research as being one of the worst areas (along with drug studies.)
    Yep that's a great article. No area of medicine makes less sense or has bigger flameouts than studies that try to pin common diseases in young people on heredity.

    A comprehensive review of genetic association studies.

    We find that over 600 positive associations between common gene variants and disease have been reported; these associations, if correct, would have tremendous importance for the prevention, prediction, and treatment of most common diseases. However, most reported associations are not robust: of the 166 putative associations which have been studied three or more times, only 6 have been consistently replicated. Interestingly, of the remaining 160 associations, well over half were observed again one or more times. We discuss the possible reasons for this irreproducibility and suggest guidelines for performing and interpreting genetic association studies. In particular, we emphasize the need for caution in drawing conclusions from a single report of an association between a genetic variant and disease susceptibility.
    The theory of natural selection suggests that genes that trigger disease will be rare. 20 years of research confirms it. When young people get sick it's because something happened to them.
    Last edited by Dingo; 01-30-2011 at 02:24 PM.

  15. #45
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    OK Sharon...there you go with your "pubs" again...
    i believe it was at least a year ago that i requested we find some pubs...
    but they have to be the kind that serve vodka!

    one of the many things more fun than "dry" research... is a "dry" martini!

    jess

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