5 ms·

Some thoughts on this as someone working on circulating-tumor DNA for the last decade or so: - Sure, cancer can develop years before diagnosis. Pre-cancerous c

Some thoughts on this as someone working on circulating-tumor DNA for the last decade or so: - Sure, cancer can develop years before diagnosis. Pre-cancerous clones harboring somatic mutations can exist for decades before transformation into malignant disease. - The eternal challenge in ctDNA is achieving a "useful" sensitivity and specificity. For example, imagine you take some of your blood, extract the DNA floating in the plasma, hybrid-capture enrich for DNA in cancer driver genes, sequence super deep, call variants, do some filtering to remove noise and whatnot, and then you find some low allelic fraction mutations in TP53. What can you do about this? I don't know. Many of us have background somatic mutations speckled throughout our body as we age. Over age ~50, most of us are liable to have some kind of pre-cancerous clones in the esophagus, prostate, or blood (due to CHIP). Many of the popular MCED tests (e.g. Grail's Galleri) use signals other than mutations (e.g. methylation status) to improve this sensitivity / specificity profile, but I'm not convinced its actually good enough to be useful at the population level. - The cost-effectiveness of most follow on screening is not viable for the given sensitivity-specificity profile of MCED assays (Grail would disagree). To achieve this, we would need things like downstream screening to be drastically cheaper, or possibly a tiered non-invasive screening strategy with increasing specificity to be viable (e.g. Harbinger Health).

tptacek 1y ago
This seems like yet another place where the base rate is going to fuck us: intuitively (and you've actually thought about this problem and I haven't) I'd expect that even with remarkably good tests, most people who come up positive will not go on to develop related disease.
- rscho 1y ago
  Ideally, you'd want a test (or two sequential ones) that's both very sensitive (rule candidates in) and specific (rule healthy peeps out). But that's only the first step, because there's no point knowing you're sick (from the populational and economic pov) if you can't do something useful about it. So you also have to include downstream tests and treatments in your assessment and all this suddenly becomes a very intricate probability network needing lots of data and thinking before decisions are made. And then, there's politics...
- Spooky23 1y ago
  You might be able to target and preemptively treat some aggressive cancers! I lost my wife to melanoma that metastasized to her brain after cancerous mole and margin was removed 4 years earlier. They did due diligence and by all signs there was no evidence of recurrence, until there was. They think that the tumor appeared 2-3 months before symptoms (headaches) appeared, so it was unlikely that you’d discover it otherwise. With something like this, maybe you could get lower dose immunotherapy that would help your body eradicate the cancer?
  - tptacek 1y ago
    I'm so sorry about your wife. Literally anything that reduces cancer deaths is a win. I'm certainly not campaigning against early detection tests like this! Just talking about a challenge that comes up operationalizing them.
    - Spooky23 1y ago
      No worries. I did not take it that way! There’s definitely a line with this stuff where there’s no benefit. But if we can eliminate deadly cancers where detection is difficult, we’ve saved the lives of thousands of people.
ada1981 1y ago
It could motivate to shift to plant based diet; start meditating; stop drinking; begin regular 5-7 day fasts; etc.
zaptheimpaler 1y ago
I guess the problem is a mismatch between detection capability and treatment capability? We seem to be getting increasingly good at detecting precancerous states but we don't have corresponding precancer treatments, just the regular cancer treatments like chemo or surgery which are a big hit to quality of life, expensive, harmful etc. Like if we had some kind of prophylactic cancer treatment that was easy/cheap/safe enough to recommend to people even on mild suspicion of cancer with false positives, we could offer it to positive tests. Maybe even just lifestyle interventions if those are proven to work. That's probably very difficult though, just dreaming out loud.
- pas 1y ago
  do the chemo medications not do anything useful at low(er) doses in these precancerous situations?
  - voiprodrigo 1y ago
    I think chemo in general kills rapidly dividing cells, which is a characteristic of cancer cells and, unfortunately, many types of regular cells as well, hence many of the side effects, like hair loss. If it is precancerous, then probably it’s not yet dividing in that way, so probably wouldn’t make much of a difference, unless you’d actually catch the moment when the switch to full fledged malignant happens.
  - stubish 1y ago
    Chemo poisons the whole body in an attempt to destroy the cancer before the treatment kills the person. Not something you would want to do precancerous I suspect. Many of the targeted treatments we now have would also not be suitable, as they can't target (or find) a cancer so small as to be deemed precancerous. But I imagine some treatments would, such as drugs targeting the cancer DNA.
- amy_petrik 1y ago
  >I guess the problem is a mismatch between detection capability and treatment capability? the problem is you do the test for 7 billion people, say, 30 times over their life... 210000000000 tests. imagine how many false negatives and false positives, the cost of follow up testing only to find... false positive. the cost of telling someone they have cancer when they don't. the anger of telling someone they are free of cancer, only to find out they had it all along this tech isn't that good, nowhere near it, more like a 1 in 100 or 10 in 100 rate of "being wrong". those numbers can get cheesed towards more false positives or false negatives. as for grail, they tried to achieve this and printed OK numbers... ... .. but their test set was their training set. so the performance metrics went to shit when they rolled it out to production
eps 1y ago
> due to CHIP What is CHIP?
- biotechbio 1y ago
  https://en.wikipedia.org/wiki/Clonal_hematopoiesis https://en.wikipedia.org/wiki/Clonal_hematopoiesis
- bglazer 1y ago
  Clonal hematopoiesis of indeterminate potential. It’s when bone marrow cells acquire mutations and expand to take up a noticeable proportion of all your bone marrow cells, but they’re not fully malignant, expanding out of control.
ajb 1y ago
Here's what may seem like an unrelated question in response: how can we get 10^7+ bits of information out of the human body every day? There are a lot of companies right now trying to apply AI to health, but what they are ignoring is that there are orders of magnitude less health data per person than there are cat pictures. (My phone probably contains 10^10 bits of cat pictures and my health record probably 10^3 bits, if that). But it's not wrong to try to apply AI, because we know that all processes leak information, including biological ones; and ML is a generic tool for extracting signal from noise, given sufficient data. But our health information gathering systems are engineered to deal with individual very specific hypotheses generated by experts, which require high quality measurements of specific individual metrics that some expert, such as yourself, have figured may be relevant. So we get high quality data, in very small quantities -a few bits per measurement. Suppose you invent a new cheap sensor for extracting large (10^7+ bits/day) quantities of information about human biochemistry, perhaps from excretions, or blood. You run a longitudinal study collecting this information from a cohort and start training a model to predict every health outcome. What are the properties of the bits collected by such a sensor, that would make such a process likely to work out? The bits need to be "sufficiently heterogeneous" (but not necessarily independent) and their indexes need to be sufficiently stable (in some sense). What is not required if for specific individual data items to be measured with high quality. Because some information about the original that we're interested in (even though we don't know exactly what it is) will leak into the other measurements. I predict that designs for such sensors, which cheaply perform large numbers of low quality measurements are would result in breakthroughs what in detection and treatment, by allowing ML to be applied to the problem effectively.
- gleenn 1y ago
  Someone should add a sensor to all those diabetes sensors people have in their arms all day and collect general info. It would obviously bias towards diabetics but that's like half the US population anyways so maybe it wouldn't matter that much.
- rscho 1y ago
  Last time someone tried to inject chips into the bloodstream, public opinion didn't handle it too well. It's the same as we would learn a lot by being more cruel to research animals. But most people have other priorities. Good or bad ? Who knows ? Research meets social constructs.
ethan_smith 1y ago
The sensitivity challenge is compounded by the signal-to-noise ratio problem at ultra-low allelic fractions (<0.1%), where technical artifacts from library preparation and sequencing can mask true variants.
edwardog 1y ago
Would you say ctDNA tools are sensitive and specific enough now to be able to make a decision about post op adjuvant therapies? “Now that I’ve had surgery, did the R0 resection get it all, or do I need to do chemo and challenging medication like mitotane?”
- mbreese 1y ago
  I’ve seen it most commonly thought of as using ctDNA to detect relapse earlier. So, more like — did the tumor come back? And if that does happen, with ctDNA, can you detect that there is a relapse before you would otherwise find it with standard imaging. Most studies I’ve seen have shown that this happens and ctDNA is a good biomarker for early detection of relapse. The case for proactively looking for circulating tumor DNA without an initial diagnosis or underlying genetic condition is a bit dicier IMHO. For example, what if really like to know (I haven’t read this article, but I’m pretty familiar with the field) is how many people had a detectable cancer in their plasma (ctDNA), but didn’t receive a cancer diagnosis. It’s been known for a while that you can detect precancerous lesions well before a formal cancer diagnosis. But, what’s still an open question AFAIK, is how many people have precancerous lesions or positive ctDNA hits that don’t form a tumor? (I’ve done a little work in this area)
- refurb 1y ago
  It seems like adjuvant treatment is rather routine at this point? And the question would be “do I believe the test when it tells me the cancer is gone?” When you know it’s not 100% accurate? Or do you always do the adjuvant treatment considering the very small chance the test is wrong has a very high cost (death)?
mapt 1y ago
This sort of thing is exactly like preventative whole body MRI scans. It's very noisy, very overwhelming data that is only statistically useful in cases we're not even sure about yet. To use it in a treatment program is witchcraft at this moment, probably doing more harm than good. It COULD be used to craft a pipeline that dramatically improved everyone's health. It would take probably a decade or two of testing (an annual MRI, an annual sequencing effort, an annual very wide blood panel) in a longitudinal study with >10^6 people to start to show significant reductions in overall cancer mortality and improvements in diagnostics of serious illnesses. The diagnostic merit is almost certainly hiding in the data at high N. The odds are that most of the useful things we would find from this are serendipitous - we wouldn't even know what we were looking at right now, first we need tons of training data thrown into a machine learning algorithm. We need to watch somebody who's going to be diagnosed with cancer 14 years from now, and see what their markers and imaging are like right now, and form a predictive model that differentiates between them and other people who don't end up with cancer 14 years from now. We [now] have the technology for picking through complex multidimensional data looking for signals exactly like this. In the meantime, though, you have to deal with the fact that the system is set up exclusively for profitable care of well-progressed illnesses. It would be very expensive to run such a trial, over a long period of time, and the administrators would feel ethically bound to unblind and then report on every tiny incidentaloma, which completely fucks the training process. This US is institutionally unable to run this study. The UK or China might, though.
- aquafox 1y ago
  > This sort of thing is exactly like preventative whole body MRI scans. It's very noisy, very overwhelming data that is only statistically useful in cases we're not even sure about yet. To use it in a treatment program is witchcraft at this moment, probably doing more harm than good. The child of a friend of mine has PTEN-Hamartom-Tumor-Syndrom, a tendency to develop tumors throughout life due to a mutation in the PTEN gene. The poor child gets whole body MRIs and other check-ups every half year. As someone in biological data science, I always tell the parents how difficult it will be to prevent false positives, because we don't have a lot of data on routine full body check-ups on healty people. We just know the huge spectrum on how healthy/ok tissue looks like.
im3w1l 1y ago
Long term the goal should be to find a treatment that is safe enough and with so small side effects that it can be used for any suspicious mutations even though it may be decades away from killing you.
- aetherspawn 1y ago
  Yes.. as I read the OP post I was thinking about how many weak natural poisons (ie bloodroot) have been shown to be effective at dispersing through the body and how they might be a good treatment ie 1-2 month course of pills.
psadri 1y ago
How about tracking deltas between blood draws starting ant youngish age when things are on average presumed to be in a good state? When a new feature turns up in a subsequent blood draw, could it then be something more concerning?

tptacek 1y ago

This seems like yet another place where the base rate is going to fuck us: intuitively (and you've actually thought about this problem and I haven't) I'd expect that even with remarkably good tests, most people who come up positive will not go on to develop related disease.

rscho 1y ago
Ideally, you'd want a test (or two sequential ones) that's both very sensitive (rule candidates in) and specific (rule healthy peeps out). But that's only the first step, because there's no point knowing you're sick (from the populational and economic pov) if you can't do something useful about it. So you also have to include downstream tests and treatments in your assessment and all this suddenly becomes a very intricate probability network needing lots of data and thinking before decisions are made. And then, there's politics...
Spooky23 1y ago
You might be able to target and preemptively treat some aggressive cancers! I lost my wife to melanoma that metastasized to her brain after cancerous mole and margin was removed 4 years earlier. They did due diligence and by all signs there was no evidence of recurrence, until there was. They think that the tumor appeared 2-3 months before symptoms (headaches) appeared, so it was unlikely that you’d discover it otherwise. With something like this, maybe you could get lower dose immunotherapy that would help your body eradicate the cancer?
- tptacek 1y ago
  I'm so sorry about your wife. Literally anything that reduces cancer deaths is a win. I'm certainly not campaigning against early detection tests like this! Just talking about a challenge that comes up operationalizing them.
  - Spooky23 1y ago
    No worries. I did not take it that way! There’s definitely a line with this stuff where there’s no benefit. But if we can eliminate deadly cancers where detection is difficult, we’ve saved the lives of thousands of people.

ada1981 1y ago

It could motivate to shift to plant based diet; start meditating; stop drinking; begin regular 5-7 day fasts; etc.

zaptheimpaler 1y ago

I guess the problem is a mismatch between detection capability and treatment capability? We seem to be getting increasingly good at detecting precancerous states but we don't have corresponding precancer treatments, just the regular cancer treatments like chemo or surgery which are a big hit to quality of life, expensive, harmful etc. Like if we had some kind of prophylactic cancer treatment that was easy/cheap/safe enough to recommend to people even on mild suspicion of cancer with false positives, we could offer it to positive tests. Maybe even just lifestyle interventions if those are proven to work. That's probably very difficult though, just dreaming out loud.

pas 1y ago
do the chemo medications not do anything useful at low(er) doses in these precancerous situations?
- voiprodrigo 1y ago
  I think chemo in general kills rapidly dividing cells, which is a characteristic of cancer cells and, unfortunately, many types of regular cells as well, hence many of the side effects, like hair loss. If it is precancerous, then probably it’s not yet dividing in that way, so probably wouldn’t make much of a difference, unless you’d actually catch the moment when the switch to full fledged malignant happens.
- stubish 1y ago
  Chemo poisons the whole body in an attempt to destroy the cancer before the treatment kills the person. Not something you would want to do precancerous I suspect. Many of the targeted treatments we now have would also not be suitable, as they can't target (or find) a cancer so small as to be deemed precancerous. But I imagine some treatments would, such as drugs targeting the cancer DNA.
amy_petrik 1y ago
>I guess the problem is a mismatch between detection capability and treatment capability? the problem is you do the test for 7 billion people, say, 30 times over their life... 210000000000 tests. imagine how many false negatives and false positives, the cost of follow up testing only to find... false positive. the cost of telling someone they have cancer when they don't. the anger of telling someone they are free of cancer, only to find out they had it all along this tech isn't that good, nowhere near it, more like a 1 in 100 or 10 in 100 rate of "being wrong". those numbers can get cheesed towards more false positives or false negatives. as for grail, they tried to achieve this and printed OK numbers... ... .. but their test set was their training set. so the performance metrics went to shit when they rolled it out to production

eps 1y ago

> due to CHIP What is CHIP?

biotechbio 1y ago
https://en.wikipedia.org/wiki/Clonal_hematopoiesis https://en.wikipedia.org/wiki/Clonal_hematopoiesis
bglazer 1y ago
Clonal hematopoiesis of indeterminate potential. It’s when bone marrow cells acquire mutations and expand to take up a noticeable proportion of all your bone marrow cells, but they’re not fully malignant, expanding out of control.

ajb 1y ago

Here's what may seem like an unrelated question in response: how can we get 10^7+ bits of information out of the human body every day? There are a lot of companies right now trying to apply AI to health, but what they are ignoring is that there are orders of magnitude less health data per person than there are cat pictures. (My phone probably contains 10^10 bits of cat pictures and my health record probably 10^3 bits, if that). But it's not wrong to try to apply AI, because we know that all processes leak information, including biological ones; and ML is a generic tool for extracting signal from noise, given sufficient data. But our health information gathering systems are engineered to deal with individual very specific hypotheses generated by experts, which require high quality measurements of specific individual metrics that some expert, such as yourself, have figured may be relevant. So we get high quality data, in very small quantities -a few bits per measurement. Suppose you invent a new cheap sensor for extracting large (10^7+ bits/day) quantities of information about human biochemistry, perhaps from excretions, or blood. You run a longitudinal study collecting this information from a cohort and start training a model to predict every health outcome. What are the properties of the bits collected by such a sensor, that would make such a process likely to work out? The bits need to be "sufficiently heterogeneous" (but not necessarily independent) and their indexes need to be sufficiently stable (in some sense). What is not required if for specific individual data items to be measured with high quality. Because some information about the original that we're interested in (even though we don't know exactly what it is) will leak into the other measurements. I predict that designs for such sensors, which cheaply perform large numbers of low quality measurements are would result in breakthroughs what in detection and treatment, by allowing ML to be applied to the problem effectively.

gleenn 1y ago
Someone should add a sensor to all those diabetes sensors people have in their arms all day and collect general info. It would obviously bias towards diabetics but that's like half the US population anyways so maybe it wouldn't matter that much.
rscho 1y ago
Last time someone tried to inject chips into the bloodstream, public opinion didn't handle it too well. It's the same as we would learn a lot by being more cruel to research animals. But most people have other priorities. Good or bad ? Who knows ? Research meets social constructs.

ethan_smith 1y ago

The sensitivity challenge is compounded by the signal-to-noise ratio problem at ultra-low allelic fractions (<0.1%), where technical artifacts from library preparation and sequencing can mask true variants.

edwardog 1y ago

Would you say ctDNA tools are sensitive and specific enough now to be able to make a decision about post op adjuvant therapies? “Now that I’ve had surgery, did the R0 resection get it all, or do I need to do chemo and challenging medication like mitotane?”

mbreese 1y ago
I’ve seen it most commonly thought of as using ctDNA to detect relapse earlier. So, more like — did the tumor come back? And if that does happen, with ctDNA, can you detect that there is a relapse before you would otherwise find it with standard imaging. Most studies I’ve seen have shown that this happens and ctDNA is a good biomarker for early detection of relapse. The case for proactively looking for circulating tumor DNA without an initial diagnosis or underlying genetic condition is a bit dicier IMHO. For example, what if really like to know (I haven’t read this article, but I’m pretty familiar with the field) is how many people had a detectable cancer in their plasma (ctDNA), but didn’t receive a cancer diagnosis. It’s been known for a while that you can detect precancerous lesions well before a formal cancer diagnosis. But, what’s still an open question AFAIK, is how many people have precancerous lesions or positive ctDNA hits that don’t form a tumor? (I’ve done a little work in this area)
refurb 1y ago
It seems like adjuvant treatment is rather routine at this point? And the question would be “do I believe the test when it tells me the cancer is gone?” When you know it’s not 100% accurate? Or do you always do the adjuvant treatment considering the very small chance the test is wrong has a very high cost (death)?

mapt 1y ago

This sort of thing is exactly like preventative whole body MRI scans. It's very noisy, very overwhelming data that is only statistically useful in cases we're not even sure about yet. To use it in a treatment program is witchcraft at this moment, probably doing more harm than good. It COULD be used to craft a pipeline that dramatically improved everyone's health. It would take probably a decade or two of testing (an annual MRI, an annual sequencing effort, an annual very wide blood panel) in a longitudinal study with >10^6 people to start to show significant reductions in overall cancer mortality and improvements in diagnostics of serious illnesses. The diagnostic merit is almost certainly hiding in the data at high N. The odds are that most of the useful things we would find from this are serendipitous - we wouldn't even know what we were looking at right now, first we need tons of training data thrown into a machine learning algorithm. We need to watch somebody who's going to be diagnosed with cancer 14 years from now, and see what their markers and imaging are like right now, and form a predictive model that differentiates between them and other people who don't end up with cancer 14 years from now. We [now] have the technology for picking through complex multidimensional data looking for signals exactly like this. In the meantime, though, you have to deal with the fact that the system is set up exclusively for profitable care of well-progressed illnesses. It would be very expensive to run such a trial, over a long period of time, and the administrators would feel ethically bound to unblind and then report on every tiny incidentaloma, which completely fucks the training process. This US is institutionally unable to run this study. The UK or China might, though.

aquafox 1y ago
> This sort of thing is exactly like preventative whole body MRI scans. It's very noisy, very overwhelming data that is only statistically useful in cases we're not even sure about yet. To use it in a treatment program is witchcraft at this moment, probably doing more harm than good. The child of a friend of mine has PTEN-Hamartom-Tumor-Syndrom, a tendency to develop tumors throughout life due to a mutation in the PTEN gene. The poor child gets whole body MRIs and other check-ups every half year. As someone in biological data science, I always tell the parents how difficult it will be to prevent false positives, because we don't have a lot of data on routine full body check-ups on healty people. We just know the huge spectrum on how healthy/ok tissue looks like.

im3w1l 1y ago

Long term the goal should be to find a treatment that is safe enough and with so small side effects that it can be used for any suspicious mutations even though it may be decades away from killing you.

aetherspawn 1y ago
Yes.. as I read the OP post I was thinking about how many weak natural poisons (ie bloodroot) have been shown to be effective at dispersing through the body and how they might be a good treatment ie 1-2 month course of pills.

psadri 1y ago

How about tracking deltas between blood draws starting ant youngish age when things are on average presumed to be in a good state? When a new feature turns up in a subsequent blood draw, could it then be something more concerning?