Biological plausibility – a keystone of medical and vaccine research

How many times have you heard tiresome tropes about the HPV vaccine causing this or that? No matter how many times we debunk the nonsense,  it persists. One of the critical points I try to make is that before an anti-vaccine claim can be made, there has to be a biological plausibility. That is, can we establish a reasonable and plausible biological mechanism, without resorting to special pleading and pseudoscience, that can lead one from one action, say receiving a vaccine, to some result, real or imagined.

Biological plausibility is a requirement to establish that correlation means causation. It is almost an essential requirement for one to claim a causal association. But biological plausibility must be consistent with our existing knowledge of biology, chemistry, physics, and medicine. How many times has an anti-vaccine zealot tried to convince us that “mercury in vaccines causes autism” but ignores the basic scientific tenets of numerous fields of biomedicine like biochemistry, cell biology, toxicology, immunology, neurology – well, just about every field?

Or someone who claims that acupuncture treats a bunch of diseases, yet we cannot find any reasonable biological plausibility between sticking a needle in the arm to treating some medical condition like pain. They tend to ignore that by using their own personal anecdote as “proof.”

That’s why science is much harder than what is said by the pseudoscience pushers. Establishing plausibility requires a strong knowledge of science to make the case. It’s much more than simply stating that plausibility does exist, you have to use actual real science, published in real scientific journals, to make the case.

So let’s talk a little bit about causality. And a large dose of biological plausibility.

Establishing causation

I’ve written about correlation, causality, and plausibility before, but I’ve never felt that I made the case appropriately. So I started to investigate more about how we determine when a correlation is equivalent to causation, and I saw that some researchers use something called the Bradford Hill criteria.

English statistician Sir Austin Bradford Hill was interested in developing a set of objective criteria that could be used to provide epidemiological evidence of causality between a cause and effect. It serves as a sort of checklist for scientists who can take data that establishes correlation and then logically determine if that supports causality.

He used his criteria to establish that smoking was linked to lung cancer (and other diseases). He essentially went through each point of his criteria to show how smoking and cancer were linked.

The Bradford Hill criteria include the following points:

  1. Strength (effect size)– this is one of the important parts of this criteria – the larger the effect from the cause, the higher the probability of a causal link. This doesn’t mean small effects aren’t important, it’s just that fields like science-based medicine favor larger effects.
  2. Consistency (reproducibility) – proposed causality needs to be observed in more than just one location. Consistent data published by different researchers in different locations with different population samples strengthen the possibility that there is a link between a cause and effect.
  3. Specificity – causation requires a very specific population with a very specific disease with no other possible explanations of that causation. Again, the more specific an association is between cause and effect, the larger the possibility of a causal link.
  4. Temporality – the proposed effect must occur after the cause, and within a likely time period for which a link between cause and effect.
  5. Biological gradient – there must be some sort of dose-response effect, that is, the higher the exposure to some cause should generally lead to a higher incidence of the effect. (There are cases where a lower exposure leads to a higher incidence, so we should observe the inverse effect.)
  6. Biological plausibility – as we will discuss next, there must be a biologically plausible mechanism between cause and effect. Of course, it is possible that we lack knowledge of all aspects of a biologically plausible mechanism between some cause and effect. Even then, the potential new mechanism must not violate basic principles of biology, chemistry, and physics.
  7. Coherence – does the proposed cause and effect fit with what we know about the disease.
  8. Experiment – does a group that lacks exposure to the effect exhibit a different outcome?

Bradford Hill developed this checklist over 50 years ago, so you could assume that there has been some evolution to the list. Some people have added one or two items to the list, like examining confounding factors and experimental bias. Those are usually evaluated in the original epidemiological research that establishes correlation, but if not, they become an unofficial part of the checklist.

These criteria should be used as a checklist. The more points that you can check off, the closer you can come to support a claim that there is a causal link between cause and observed effect.

Bradford Hill criteria – vaccines and autism

Let’s take a look at the hypothesized effect between vaccines and autism spectrum disorder (ASD), which has been thoroughly debunked by scientific research. How do the observations of vaccines and autism fit within the Bradford Hill criteria?

It’s hard to do this exercise since we know the outcome – there is no correlation or causation. But it’ll be a good intellectual exercise.

  1. Strength – there is simply little robust, unbiased published evidence that establishes a higher incidence of autism in vaccinated children than in unvaccinated children. So the strength of the association is nearly non-existent.
  2. Consistency – actually, the only consistent evidence is supporting the null hypothesis, that is, that vaccines are not linked to autism. There is little evidence of correlation, let alone consistent evidence of causation.
  3. Specificity – the claimed link between vaccines and autism may appear to meet the criteria of specificity, but remember, autism spectrum disorder is a wide range of neurodevelopmental changes that can be quite dissimilar.
  4. Temporal – some observations meet the temporal criteria, but it’s difficult to establish at what point a cause and effect are within some logical time frame. The people pushing the narrative about vaccines and ASD seem to think that the appearance of the symptoms of ASD at any point post-vaccine should be included. That’s not good science.
  5. Biological gradient – there just isn’t any robust published evidence of some sort of dose-response relationship between vaccines and ASD. If the supporters of the claim had strong evidence that the more vaccines a child gets, the higher the risk of ASD, we could check this criterion off for the link. But we can’t because there is no data supporting a biological gradient.
  6. Biological plausibility – this becomes one of the central issues of trying to determine if there is a link between vaccines and ASD. We don’t know a lot about the pathophysiology of ASD, but there is overwhelming evidence that it has a very strong genetic component. There just isn’t a biologically plausible mechanism that can lead from vaccines to ASD. The anti-vaccine squad loves to propose mechanisms that not only aren’t plausible but require significant changes in our understanding of human physiology. For example, we understand that aluminum burden in children is 99.999999% from inhaled and consumed aluminum – yet the anti-vaccine zealots want us to believe that intramuscular injection of a sub-biological amount of aluminum somehow is more important than all other sources of the element, and only the aluminum from vaccines leads to autism. That is the definition of biologically implausible.
  7. Coherence – as we stated in biological plausibility, our understanding of ASD leads us to one basic idea – the initial symptoms occur at the same time as vaccines. And ASD has a large genetic component that is not induced by vaccines, which has only one effect – on the immune system.
  8. Experiment – once again, there is just no robust published evidence that shows that the non-vaccinated population has some lower risk of ASD. In fact, affirmative evidence is that they are almost the same.

Thus, at best, the claim that there is a link between vaccines and autism barely meets one of the Bradford Hill criteria – temporal. And even there, we cannot establish what defines temporal, if there were an association.

To me, the largest issue I have with the anti-vaccine claim about autism is biological plausibility. They keep moving the goalposts to try to twist logic into a pretzel to convince us of biological plausibility. They first claimed it thiomersal. Then aluminum. Then some random ingredients of the vaccine.

The only biologically plausible link to ASD is genetics. And it meets almost all of the Bradford Hill criteria. Imagine that.

Biological plausibility in detail

In epidemiology, biological plausibility ranks near the top of the list of criteria to make a claim of causality between cause and effect. This is something that is forgotten or intentionally ignored by those pushing a pseudoscience belief.

Biological plausibility is a major component of the method of logic that is used to establish a cause-and-effect relationship between a biological factor and a particular disease or adverse event. You might think that I only use plausibility to reject a claim, but it really is important to the determination whether a proposed therapy has benefit to a patient.

We understand how vaccines induce the immune system to remember a pathogen and destroy it if it encounters it again. We understand how an anti-depressant affects the biochemistry of neurons to adjust mood disorders. We understand how thalidomide, once considered one of the most dangerous drugs on the market, is highly effective in treating multiple myelomas.

Biological plausibility is a fundamental part of the drug discovery process. There is a belief that Big Pharma tosses every chemical on the planet at every disease to find if it works or not. In reality, because they generally understand the pathophysiology of most diseases, they can logically and plausibly choose a treatment that could affect a change.

On the other hand, the lack of biological plausibility is why we reject claims about acupuncture, homeopathy, and much other complementary and alternative medicine (CAM) quackery. Even if there is some small placebo (or nocebo) effect, it is implausible to believe that these quack treatments could have any causal effect.


No matter what you want to believe about any medical quackery, no matter how hard you want to convince yourself they are real, and no matter how much you want everyone to believe your anecdotes, if you cannot establish biological plausibility with substantial scientific evidence, you’ll never be able to establish a link.

And the same is true of vaccine adverse effects. If you cannot establish a reasonable level of biological plausibility, based on published scientific evidence, then it becomes difficult to accept a link between vaccines and anything. I think if you’re an anti-vaccine religion adherent before you can make any other argument, you need to provide us with biological plausibility (along with the rest of Bradford Hill criteria) before you make any other argument.

Recently, there has been a lot of claims that mobile phones cause cancer or other diseases. The pushback has been powerful – it starts with a lack of biological plausibility.

Too often, we let those who push pseudoscience invent some magical therapy (or magical adverse events, in the case of anti-vaccine zealots) without pinning them down to provide us very specific information on why there is a causal link. I think if you’re going to claim that acupuncture does anything or that vaccines cause autism, you need to write a 20-page paper outlining the scientific evidence that supports the biological plausibility of the claim. I won’t hold my breath.



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The Original Skeptical Raptor
Chief Executive Officer at SkepticalRaptor
Lifetime lover of science, especially biomedical research. Spent years in academics, business development, research, and traveling the world shilling for Big Pharma. I love sports, mostly college basketball and football, hockey, and baseball. I enjoy great food and intelligent conversation. And a delicious morning coffee!