Pandemic Prediction Checklist: H5N1
Pandemic Prediction Checklist: Monkeypox
I have lost my trust in this community’s epistemic integrity, no longer see my values as being in accord with it, and don’t see hope for change. I am therefore taking an indefinite long-term hiatus from reading or posting here.
Correlation does imply some sort of causal link.
For guessing its direction, simple models help you think.
Controlled experiments, if they are well beyond the brink
Of .05 significance will make your unknowns shrink.
Replications prove there's something new under the sun.
Did one cause the other? Did the other cause the one?
Are they both controlled by something already begun?
Or was it their coincidence that caused it to be done?
Fungal infections are clearly associated with cancer. There's some research into its possible carcinogenic role in at least some cancers. There's a strong consensus that certain viruses can, but usually don't, cause cancer. Personally, it seems like a perfectly reasonable hypothesis that fungal infections can play an interactive causal role in driving some cancers. In general, the consensus is you typically need at least two breakdowns of the numerous mechanisms that regulate the cell cycle and cell death for cancer to occur.
I'm a PhD student in the cancer space, focusing on epigenetics and cancer. Basically, this is the field where we try to explain both normal cellular diversity (where DNA mutations are definitely not the cause except in very specialized contexts like V(D)J recombination) and cancers apparently not driven by somatic mutations in protein-coding genes.
Mutations not in protein-coding genes are not necessarily inert. RNA can be biologically active. Noncoding DNA serves as docking sites for proteins, which can then go on to affect transcription of genes into mRNA. The proteome can also be affected by alternative splicing of mRNA. Non-coding mutations can potentially affect any of these processes and thereby affect the RNA and protein landscape within a cell.
In 2024, our ability to detect mutations varies widely across the genome, due both to the way we obtain sequencing data in the first place and the way we attempt to make sense of it. NGS sequencing involves breaking the genome into short fragments and reading around 150 base pairs on either end of the fragments, then trying to map it back to a reference genome. Mapping quality will suffer or completely degrade both if the patient has substantial genetic difference from the reference genome or in regions that are highly repetitive within the genome, such as centromeres. When I work with genetic data, there are regions spanning multiple megabasis that are completely blank, and a large percentage of our reads have to be thrown out because we can't unambiguously map them to a particular location on the genome. This will be partially overcome in the future as we start to use more long-read sequencing, but this technology is still in its early stages and I'm not sure it will completely replace NGS for the foreseeable future.
In the epigenetics space, we focus on several aspects of cell biochemistry apart from DNA mutations. The classic example is DNA methylation, which is a methyl group (basically a carbon atom) present on about 60% of cytosines (C) that are immediately followed by guanine (G). The CpG dinucleotide is heavily underrepresented relative to what you'd expect by chance, and its heavily clustered in gene promoters. Methylated CpG islands in promoters are associated with "off genes". The methylation mark is preserved across mitosis. It's thought to be a key mechanism by which cell differentiation is controlled. We also study things like chromatin accessibility (whether DNA is tightly packaged up and relatively inaccessible to protein interactions or loose and open) and chromatin conformation (the 3D structure of DNA, which can control things like subregion localization into a particular biochemical gradient or adjacency of protein-docking DNA regions to gene promoters).
These epigenetic alterations are also thought to be potentially oncogenic. Epigenetic alterations could potentially occur entirely due to random events localized to the cell in which the alterations occur, or could be influenced by intercellular signaling, physical forces, or, yes, infection. If fungal infections control cells like puppets and somehow cause cancer, my guess is that it would be through some sort of epigenetic mechanism (I don't know if there are any known fungi that can transmit their DNA to human cells).
Epigenetics research is mainstream, but the technology and data analysis is comparatively immature. One of the reasons it's not more common is that it's much harder to gather data on and interpret than it is to study DNA mutations. Most of our epigenetics methods involve sequencing DNA that has undergone some extra-fancy processing of one kind or another, so it's bound to be strictly more expensive and difficult to execute than plain ol' DNA sequencing alone. Compounding this, the epigenetic effects we're interested in are typically different from cell to cell, meaning that not only do you have these extra-challenging assays, you also need to aim for single-cell resolution, which is also either extremely expensive (like $30/cell, isolating individual nuclei using a cell sorter and running reactions on each individually, leading to assays that can cost millions of dollars to produce) or difficult (like using a hyperactive transposase to insert DNA barcodes into intact nuclei that give a cell-specific label the genetic fragments originating from each cell, bringing assay costs down to a mere $50,000-$100,000 driven mainly by DNA sequencing rather than cell processing costs). This data is then very sparse (because there's a finite amount of genetic information in each cell), very large, and very difficult to interpret. We also have extremely limited technologies to cause specific epigenetic changes, whereas we have a wide variety of tools for precisely editing DNA.
For potentially oncogenic infections, fungal or otherwise, you'd want to show things like:
All of this seems like a perfectly respectable research project, just difficult. I can't imagine anybody I work with having a problem with it. Where they probably would have a problem would be if the argument was that "fungal infections are the sole cause of cancer, and DNA mutations or epigenetic alterations are completely irrelevant to oncogenesis."
There's an angle I've neglected in this post until now, which is the perspective from evolutionary theory. it's more common to refer to this in explaining how cancer evolves within an individual. But it's also relevant to consider how it bears on the Peto paradox. Loosely, species tend to evolve such that causes of reproductive unfitness (including death) tend to balance out in terms of when they occur in the life cycle. Imagine a species under evolutionary pressure to grow larger, perhaps because it will allow it to escape predation or access a new food source. If the larger number of cells put it at increased risk of cancer, then at some point there would be an equilibrium where the benefit of increased size was cancelled by the cost of increased oncogenesis risk. This also increases adaptive pressure to stabilize new oncopreventative mechanisms in the population that weren't present before. This may facilitate additional growth to a new equilibrium.
This helps explain why cancer isn't associated with larger size: adaptive pressure to develop new oncopreventative mechanisms increases in proportion to the risk to reproductive fitness posed by cancer.
I think it’s worth asking why people use dangling questions.
In a fun, friendly debate setting, dangling questions can be a positive contribution. It gives them an opportunity to demonstrate competence and wit with an effective rejoinder.
In a potentially litigious setting, framing critiques as questions (or opinions), rather than as statements of fact, protect you from being convicted of libel.
There are situations where it’s suspicious that a piece of information is missing or not easily accessible, and asking a pointed dangling question seems appropriate to me in these contexts. For certain types of questions, providing answers is assigned to a particular social role, and asking a dangling question can be done to challenge to their competence or integrity. If the question-asker answered their own question, it would not provide the truly desired information, which is whether the party being asked is able to supply it convincingly.
Sometimes, asking dangling questions is useful in its own right for signaling the confidence to criticize or probing a situation to see if it’s safe to be critical. Asking certain types of questions can also signal one’s identity, and this can be a way of providing information (“I am a critic of Effective Altruism, as you can see by the fact that I’m asking dangling questions about whether it’s possible to compare interventions on effectiveness”).
In general, I think it’s interesting to consider information exchange as a form of transaction, and to ask whether a norm is having a net benefit in terms of lowering those transactions costs. IMO, discourse around the impact of rhetoric (like this thread) is beneficial on net. It creates a perception that people are trying to be a higher-trust community and gets people thinking about the impact of their language on other people.
On the other hand, I think actually refereeing rhetoric (ie complaining about the rhetoric rather than the substance in an actual debate context) is sometimes quite costly. It can become a shibboleth. I wonder if this is a systemic or underlying reason why people sometimes say they feel unsafe in criticizing EA? It seems to me a very reasonable conclusion to draw that there’s an “insider style,” competence in which is a prerequisite for being treated inclusively or taken seriously in EA and rationalist settings. It’s meant well, I think, but it’s possible it’s a norm that benefits some aspects of community conversation and negatively impacts others, and that some people, like newcomers/outsiders/critics are more impacted by the negatives than they benefit from the positives.
Preliminary data from pooled tank samples (you collect between the truck that sucks it out of the planes and the dumping point) looks very good.
Setting aside economics or technology, would it in principle be possible to detect a variant of concern in flight and quarantine the passengers until further testing could be done?
Sorry to keep harping in this, but 0.2% of wastewater from people who've ever been infected (cumulative incidence) not currently infected (prevalence).
I appreciate the harping! So you're saying that your prelim results show that 0.2% of the sampled population would need to have at some point in the past been infected for the variant of concern to be detectable?
Gotcha. Last I emailed Kevin he was suggesting this would be deployed in airports rather than municipalities. So the plan has changed?
It’s true only a fraction of travelers defecate, but it still seems like you’d need an average of about 300 infected travelers/day in an airport setting to get .2% of the wastewater being from them? Or in a city of 1 million people, you’d need something like 2,000 infected?
Is that 0.2% of people “contributing” to the wastewater? Ie if deployed in an airport, approximately 0.2% of daily airport users being infected might be the threshold for detection? If so, at SeaTac, that would mean around 300 infected users per day would be required to trigger the NAO if I am understanding you correctly.
Because those are unsupported claims about his character, while noting his conviction (particularly given that he was covering up an affair) is specific evidence of his bad character. Moreover, it is evidence of a particular way in which his character is bad - he is not only willing to have an affair, but he’s willing to break the law to hide it.
If I tell you X is a bad person, that tells you nothing except my opinion of them. If I say “they were recently convicted of a felony for falsifying business records covering up an affair,” you can judge for yourself whether or not you think this fact reflects on their character or is worthy of punishment (ie by denying them your vote for President).
I think this post might be a good illustration of the sticker shortcut fallacy I'm describing. Instead of directly describing the information you want to impart, you're instead relying upon the label dredging up enough 'good enough' connotations attached to it.
I disagree. The label 'dredges up' (implies) a sound argument. One syllogism that might be implied by "Trump: convicted felon" is something like this:
A person who has been convicted of a felony is unfit to serve as president.
Donald Trump has been convicted of felony in the Stormy Daniels case.
Therefore, Donald Trump is unfit to serve as president.
This is a valid syllogism, though you may reject the premise. I don’t think it qualifies as deceptively bad. It could be false but popular, but that has to be argued.
There are several non-fallacious reasons to emphasize Trump's status as a convicted felon:
Calling MLK a 'criminal' doesn't evoke the same whiff of hypocrisy and contradiction, because civil rights activists have rarely if ever based their moral argument on 'law and order' rhetoric. Indeed, most Black Americans agree "the criminal justice system was designed to hold Black people back." Pointing out MLK was a criminal, given the nature of the "crime," just lends further support to their argument.
Using repetitive speech can also cause people to zone out, irritate them, or make them think you're being forgetful.
Repetitive speech and other simplification tactics can also backfire. For example, if you try to oversimplify your presentation so that 'everyone can understand,' not realizing that a small core of fellow experts wanted and could have handled much more detail, while the majority weren't going to follow you (or care) no matter how much you simplified. If people then see you do this (performing pedagogy rather than inter-expert discourse), it can be seen as a misjudgment about the purpose of the event and the desires of the audience.
Repetitive speech has its uses, but it's important to be thoughtful about context, your goals, and the goals of your audience.
I think the answer is simply that the modern world allows people to live with poverty rather than dying from it. It’s directly analogous to, possibly caused by, the larger increase in lifespan over healthspan and consequent failure of medicine to eliminate sickness. We have a lot of sick people who’d be dead if it weren’t for modern medicine.