4 ms·

Does that invalidate any studies on treatments for Alzheimer? If it turns out many people who show symptoms don't actually have it, it's no wonder that a treatm

Does that invalidate any studies on treatments for Alzheimer? If it turns out many people who show symptoms don't actually have it, it's no wonder that a treatment is so hard to find.

carbocation 9y ago
It reduces these studies' power to detect results. If you thought you had 100 cases and 100 controls, it turns out perhaps you really had 30 cases and 100 controls, and 70 controls misclassified as cases. Power is going to be substantially hurt.
- gwern 9y ago
  I could see it having more implications than just measurement error reducing power. It's entirely plausible that a drug which has an effect on Alzheimers would come with side-effects that would damage those who just have senile dementia; imagine a drug which dissolves amyloid plaques while doing some moderate damage, in a trial with a mix of dementia and Alzheimers, the Alzheimers getting better is masked by the dementia ones getting worse, for a net average zero compared to the placebo group.
- PeterisP 9y ago
  However, it may significantly increase the size of measured effect if you can go back and re-classify the patients - in your example, it may turn an earlier study where only 30 of 100 cases showed improvement to a study where 30 of 30 cases responded to treatment well.
- std_throwaway 9y ago
  Those 70 are not controls but each may have a different disease.
mannykannot 9y ago
There seem to be a lot of loose ends in this article: how many of these patients will go on to develop Alzheimer's? On what basis are the current treatments for Alzheimer's considered to be effective, if we did not previously have a test to determine who has developed it? On what basis would the physicians whose patients were enrolled in this study change their care plans, and in what way? At one point, the article says "A positive test for amyloid does not mean someone has Alzheimer’s... But a negative test definitively means a person does not have it". To me, there seems to be a hint of "these patients' condition does not fit the dictionary definition of Alzheimer's, so clearly it would be wrong to treat them as if they had it", yet the article seems to leave open the door to the possibility that it is the progression of Alzheimer's that is not fully understood. I hope an expert can chime in and set me straight.
- SAI_Peregrinus 9y ago
  Not an expert, but I read Derek Lowe's blog[1] and he tends to report on pretty much all the drug trials in the Alzheimer's space. The amyloid hypothesis (that the cause of Alzheimers is the buildup of beta amyloid plaques) seems pretty weak at this point. The drugs that remove or reduce amyloid buildup don't seem to stop the progression of the disease. The current best guess seems to be that the amyloid plaques are a symptom of whatever the underlying cause is. And the key takeaway is that we have NO IDEA what the actual cause is. We've got a bunch of guesses. One of them might even be right. Or possibly multiple, there are probably several diseases that cause the same symptoms. So if we can detect the non-presence of amyloid plaques but detect symptoms that would be good as a way to distinguish between the different diseases. Of course there might be more than two variants... [1] http://blogs.sciencemag.org/pipeline/archives/category/alzheimers-disease http://blogs.sciencemag.org/pipeline/archives/category/alzhe...
  - nonbel 9y ago
    I'll admit I wasn't aware in the 1980s when the hypothesis took hold, but it never seemed like a good one to me just because amyloids are so thermodynamically favored. There must be constant and diverse measures functioning correctly to avoid their formation.
    - atomical 9y ago
      Huh?
      - nonbel 9y ago
        nonbel 469 days ago [-] >"Of all the myriad way a protien can fold, it happens to find one that induces the same malformation when it interacts with another protein." It doesn't really "just happen", amyloids consist of peptides folded into beta-sheets and aggregates of these seem to be the most thermodynamically stable structures it is possible for polypeptide chains (regardless of sequence) to form: "From a wide range of in vitro experiments on peptides and proteins we now know that the formation of amyloid structures is not a rare phenomenon associated with a small number of diseases but rather that it reflects a well-defined structural form of the protein that is an alternative to the native state — a form that may in principle be adopted by many, if not all, polypeptide sequences [...] These observations, therefore, have led to the remarkable conclusion that, at the concentrations present in living systems, the native states may not always represent the absolute free energy minima of the corresponding polypeptide chains — the native form of a protein could in some cases simply be a metastable monomeric (or functionally oligomeric) state that is separated from its polymeric amyloid form by high kinetic barriers" http://www.ncbi.nlm.nih.gov/pubmed/24854788 http://www.ncbi.nlm.nih.gov/pubmed/24854788 https://news.ycombinator.com/item?id=11535494 https://news.ycombinator.com/item?id=11535494

Does that invalidate any studies on treatments for Alzheimer? If it turns out many people who show symptoms don't actually have it, it's no wonder that a treatment is so hard to find.

carbocation 9y ago

It reduces these studies' power to detect results. If you thought you had 100 cases and 100 controls, it turns out perhaps you really had 30 cases and 100 controls, and 70 controls misclassified as cases. Power is going to be substantially hurt.

gwern 9y ago
I could see it having more implications than just measurement error reducing power. It's entirely plausible that a drug which has an effect on Alzheimers would come with side-effects that would damage those who just have senile dementia; imagine a drug which dissolves amyloid plaques while doing some moderate damage, in a trial with a mix of dementia and Alzheimers, the Alzheimers getting better is masked by the dementia ones getting worse, for a net average zero compared to the placebo group.
PeterisP 9y ago
However, it may significantly increase the size of measured effect if you can go back and re-classify the patients - in your example, it may turn an earlier study where only 30 of 100 cases showed improvement to a study where 30 of 30 cases responded to treatment well.
std_throwaway 9y ago
Those 70 are not controls but each may have a different disease.

mannykannot 9y ago

There seem to be a lot of loose ends in this article: how many of these patients will go on to develop Alzheimer's? On what basis are the current treatments for Alzheimer's considered to be effective, if we did not previously have a test to determine who has developed it? On what basis would the physicians whose patients were enrolled in this study change their care plans, and in what way? At one point, the article says "A positive test for amyloid does not mean someone has Alzheimer’s... But a negative test definitively means a person does not have it". To me, there seems to be a hint of "these patients' condition does not fit the dictionary definition of Alzheimer's, so clearly it would be wrong to treat them as if they had it", yet the article seems to leave open the door to the possibility that it is the progression of Alzheimer's that is not fully understood. I hope an expert can chime in and set me straight.

SAI_Peregrinus 9y ago
Not an expert, but I read Derek Lowe's blog[1] and he tends to report on pretty much all the drug trials in the Alzheimer's space. The amyloid hypothesis (that the cause of Alzheimers is the buildup of beta amyloid plaques) seems pretty weak at this point. The drugs that remove or reduce amyloid buildup don't seem to stop the progression of the disease. The current best guess seems to be that the amyloid plaques are a symptom of whatever the underlying cause is. And the key takeaway is that we have NO IDEA what the actual cause is. We've got a bunch of guesses. One of them might even be right. Or possibly multiple, there are probably several diseases that cause the same symptoms. So if we can detect the non-presence of amyloid plaques but detect symptoms that would be good as a way to distinguish between the different diseases. Of course there might be more than two variants... [1] http://blogs.sciencemag.org/pipeline/archives/category/alzheimers-disease http://blogs.sciencemag.org/pipeline/archives/category/alzhe...
- nonbel 9y ago
  I'll admit I wasn't aware in the 1980s when the hypothesis took hold, but it never seemed like a good one to me just because amyloids are so thermodynamically favored. There must be constant and diverse measures functioning correctly to avoid their formation.
  - atomical 9y ago
    Huh?
    - nonbel 9y ago
      nonbel 469 days ago [-] >"Of all the myriad way a protien can fold, it happens to find one that induces the same malformation when it interacts with another protein." It doesn't really "just happen", amyloids consist of peptides folded into beta-sheets and aggregates of these seem to be the most thermodynamically stable structures it is possible for polypeptide chains (regardless of sequence) to form: "From a wide range of in vitro experiments on peptides and proteins we now know that the formation of amyloid structures is not a rare phenomenon associated with a small number of diseases but rather that it reflects a well-defined structural form of the protein that is an alternative to the native state — a form that may in principle be adopted by many, if not all, polypeptide sequences [...] These observations, therefore, have led to the remarkable conclusion that, at the concentrations present in living systems, the native states may not always represent the absolute free energy minima of the corresponding polypeptide chains — the native form of a protein could in some cases simply be a metastable monomeric (or functionally oligomeric) state that is separated from its polymeric amyloid form by high kinetic barriers" http://www.ncbi.nlm.nih.gov/pubmed/24854788 http://www.ncbi.nlm.nih.gov/pubmed/24854788 https://news.ycombinator.com/item?id=11535494 https://news.ycombinator.com/item?id=11535494