Written by Joe Ballenger
I’m still following the Zika/Microcephaly literature. I’m not writing about every paper which comes out, but I am writing about the ones I feel are pretty important. The most recent ‘big paper’ came out in the New England Journal of Medicine in mid-April. The paper, cited below, purports to definitively connect Zika and microcephaly.
Correlation VS Causation
When writing about medicine it’s important to separate correlation and causation, and explain why it can be complicated to separate the two. Figuring out whether one thing causes something else can be tricky, because things can be related without directly interacting.
The classic example of a correlation which isn’t causation are ice cream sales and car accidents. Ice cream sales decrease during winter, while car accidents increase. It would be-to put it lightly-a stretch to conclude that eating ice cream will protect you from car accidents. Instead, the relationship has to do with weather. Cold weather changes ice cream consumption patterns, and results in bad road conditions. So there’s a relationship there, but one doesn’t cause the other.
However, one would expect something that causes something else would have a strong correlation. A good example of this is honeybee hives and honey production. More honeybee hives means more honey production. I used the website Spurious Correlations to make a graph of this exact scenario:
In this case, the correlation explains about 67% of the data. This makes sense, because honey production depends on things like weather and availability of flowers. In other words, it varies based on a lot of things. So a correlation of 1, which would be a perfect correlation, isn’t really expected. In contrast, the number of Political Action Committees (PACs) in the US has a much higher correlation with the amount of honey produced…about 90%.
People who donate to political action committees don’t make honey, but the number of PACs is more closely correlated with honey production than honey producing bee colonies. These two things are completely unrelated.
So correlation doesn’t necessarily mean causation. However, things which have a causal relationship (e.g. one causes the other) should be correlated. Correlation is needed to prove causation, but strong correlations don’t necessarily prove causation by itself.
So this begs the question: what does prove causation?
Getting a perfect correlation from a perfect causal relationship (like the honeybee example above) is rare. In epidemiology, it’s also rare to get a slam-dunk dataset which perfectly proves a causal relationship. You need several intersecting lines of evidence.
The paper in NJEM used a series of criteria called Shepard’s Criteria, which looks at whether the following lines of data correspond with one another:
- Exposure: Does Zika virus consistently appear in microcephalic infants? Yes
Pregnant women are exposed to Zika, and replicating Zika virus has been found in microcephalic infants and the amniotic fluid of pregnant women. So the fetuses have obviously been exposed.
- Correlations: Is Zika and microcephaly consistent in time and space? Maybe
It’s already known through epidemiological studies that there is a correlation between Zika and microcephaly. It’s not strong, but there are also a lot of confounding factors.
- Consistency of symptoms and timelines from case studies: Does Zika-associated microcephaly consistently produce the same kind of microcephaly?
- The probability of the condition: Are both conditions rare enough to imply causation?
- Animal models: Can we get microcephaly to appear in a Zika-infected animal? Unknown
No animal studies have been performed yet.
- Whether a causal relationship makes sense: Does Zika infect people in a way that could cause this condition? Yes.
The association between Zika and microcephaly also makes sense from a pathology perspective, because Zika infects the brain and causes damage which could conceivably lead to microcephaly. It also infects developing human brain cells in petri dishes, and in the womb.
Conditions 1 and 6 have been found to be true already. The evidence for #2 is growing. However, the evidence for 3 and 4 lies in scattered case reports which hadn’t been compared and contrasted yet.
Are both conditions rare enough to imply causation?
I’m going to talk about #4 first, because it gives context to the case studies.
This one is based entirely on probability. Two rare events shouldn’t consistently occur together.
In order to look at this, you need a rare infection and a rare defect. Microcephaly is generally pretty rare. However, it’s more common in Brazil than it should be. Zika infection is also really common in Brazil. So this is hard to sort out in Brazil, because one of these events is very common.
However, you can look at people who vacationed in places where Zika is circulating. This is a sort of ‘natural experiment’, because you briefly expose someone to an environmental condition and then quickly remove them. Vacations are generally only a couple of weeks, so they’re not going to be exposed to a lot of environmental variables which could cause birth defects in the long-term. If there’s not a link, then Zika-associated microcephaly should be fairly rare.
Think about it this way. Zika is very rare, or even non-existent, in the places where these people are from. Microcephaly is also rare. So they shouldn’t occur together because the combination of these two things should be extremely rare. However, studies of many women who returned from vacation with Zika also found that their developing fetuses had severe birth defects: they were microcephalic.
Furthermore, there is one case where a woman’s fetus developed microcephaly after a very brief travel to a region where she caught Zika.
Does Zika-associated microcephaly consistently produce the same kind of microcephaly?
Microcephaly can be caused by many things, both genetic and environmental. There are different types of microcephaly, which result in people that look very different. In fetal alcohol syndrome, for example, microcephaly typically presents with narrow eyes, an absence of the trough which runs between the nose and mouth, and a thin upper lip. These deformities are consistent in infants born to women who drank heavily during pregnancy.
So comparing whether people infected with Zika virus have similar types of microcephaly is really informative. Looking at cases in vacationing women also has the advantage of getting rid of some of those confounding factors. Since these women are from other places, they’re not likely to be exposed to many of the risk factors Brazilians may be exposed to. Folic acid deficiency and mycotoxin exposure, for example, aren’t likely issues in travelers from wealthier countries.
Women who traveled to Zika endemic regions, and who came back with microcephalic infants, have infants who have consistent symptoms. These include overlapping skull bones, a loose scalp, and an exaggeration of the back of the head. These sorts of deformations are absent in other cases of microcephaly, except in very rare cases where the brain is severely damaged during fetal development. Interestingly, infection by cytomegalovirus can also cause this sort of deformity.
So not only is microcephaly extremely rare, the type of microcephaly that developed in infants exposed to Zika virus is also extremely rare. In fact, prior to 2001, there were only about 20 cases in the literature.
The Bottom Line
Each of these lines of evidence is weak, and can be easily dismissed when not taken into consideration with one another. Infection doesn’t mean much by itself, even if the infection is in the brain. The correlations are weak evidence…and even the intensively studied studies of single travelers are weak because the numbers are so low.
However, when taken together, the link suddenly looks stronger because these lines of evidence intersect with one another. Zika infection could hypothetically produce microcephaly, and there is a correlation between Zika and microcephaly. Microcephaly commonly appears in Zika infected vacationers, when it shouldn’t be there because it’s so rare. The very rare type of microcephaly produced by Zika virus is also consistent between different cases, and it matches up well with microcephaly caused by other pathogens. Also, those pathogens were absent in these cases.
One single line of evidence isn’t likely to prove causation. However, there are different intersecting lines of evidence which are beginning to add up to evidence of causation.
As an experimental biologist, I still do very much favor experimental evidence. I’d still like to see evidence from animal models, and natural experiments where Zika moves from one area to another.Seeing increases and decreases in microcephaly during an epidemic would be really informative, but it may take a few years to get a good series of studies done.
Despite those reservations, I do think this is enough to say that there is evidence for causation beyond a simple correlation. The evidence is still pretty weak because the studies are small, but these studies are not low-quality. I expect that bigger and stronger studies will solidify the link.
Rasmussen, S. A., Jamieson, D. J., Honein, M. A., & Petersen, L. R. (2016). Zika virus and birth defects—reviewing the evidence for causality.New England Journal of Medicine.
I’d also like to thank Mary Beth Martini-Lyons, Catherine Scott, and Dev Paudel for helping us obtain some of the information used in this article.