Correlation or causality: Why is it so tricky to link the Zika virus to microcephaly in newborn babies?

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The Zika virus has been all over the news as it has been linked to underdeveloped brains and smaller heads (a disease called microcephaly) in newborn babies in South and Central America. However, proving a causal link has been tricky.

But first things first, what do we know about the Zika virus? A brief history.

The virus belongs to the family of Flaviviruses and is spread by day-time active Aedes mosquitoes. Other well-known members of the Flavivirus family are Yellow and Dengue Fever. In contrast to these two serious and sometimes fatal diseases, Zika causes mostly no or only mild symptoms (such as a rash and mild fever). Treatment is normally simply resting up.

Discovered in the Zika forest in Uganda in 1947, the virus has been found in a narrow equatorial belt from Africa to Asia – but mainly in monkeys. Infections in humans were rarely observed before 2007, when an outbreak occurred on Yap Island of Micronesia and the virus infected 75 percent of the population. From there the virus spread east across the Pacific Ocean Island States during 2013/14 and in 2015 caused a now pandemic outbreak in Central and South America as well as the Caribbean. Given the mild symptoms this does not seem too bad, right? The problem is that the infection has now been correlated to microcephaly in newborn babies.

Due to the widespread of the virus the World Health Organisation (WHO) has declared Zika a global emergency and predicts 4 million infections in America alone! This warning and the current lack of knowledge regarding the effects of the virus on pregnancies led many countries to issue travel warnings for the affected areas. Some affected countries such as Colombia, Ecuador and Jamaica even ask women to postpone pregnancy till more is known!

What is known about the effect of the Zika virus during pregnancy?

Initial observation for a link between the virus infection and microcephaly in newborns was by correlation. During the recent Zika outbreak the number of children born with microcephaly has increased from about five cases per 100,000 live births to 200 per 100,000. While this seems like strong evidence it is important to note that this is only a correlation- and not a causal link.

And causality and correlation are not the same thing!

Causality is the abstract word for a link between two factors; in this case causality would mean that an infection with the Zika virus leads to microcephaly. But so far this has not been proven – it has only been shown that the two entities correlate, meaning we see a rise in the number of Zika infections as well as a rise in microcephaly cases. It is still unclear however if the rise in microcephaly is due to Zika infections or something else.

To help understand the difference between causality and correlation check out this website which lets you correlate random things. For example: The divorce rate in Maine with the consumption of margarine. And while less margarine consumption correlates with a drop in divorces, there is no causal link between the two measures. It just happens that both numbers fall over the years.

correlation

While the correlation between Zika and microcephaly does not proof a causal link, there is evidence suggesting causation.

  1. Other flaviviruses are known to cause microcephaly in newborn animals following an infection during pregnancy.
  2. Strikingly, a study from the 1970s revealed that the Zika virus can replicate in neurons of young mice, causing neuronal destruction. Given the low number of Zika infection at the time the study never got a lot of attention.
  3. Genetic material of the Zika virus has been detected in both the mothers and amniotic fluid surrounding the embryo suggesting that the virus can infect the unborn child.
  4. The complete genome of the virus has now also been found in brain tissue of still-born babies suffering from microcephaly. Interestingly, a different study suggests that Zika preferentially infects the brain of the embryos as the viral genome could not be detected in other organs such as the heart or lung.

What would be final proof for causality?

A so-called case-control study. In this type of study large cohorts of people are compared to assess a causal link between two factors. In this case you could enrol pregnant women in Zika-effected areas, test them for a Zika infection during their pregnancy and then compare the rates of microcephaly in babies from non-infected versus infected women. If Zika is a causal link, you would expect a larger number of microcephaly cases in the infected women. So far the correlation has been based on overall microcephaly rates in all newborns in Zika-effected areas independent of the infection status of the mother and without consideration of any other factors that may cause brain maldevelopment. So for the case-control study it is important that other factors such as age, other infections diseases and environmental factors are also correlated with microcephaly. For that matter huge cohort sizes are crucial to minimize the effect of other factors as they are likely different between the women.

Model systems are often used in science as they eliminate these “side” factors. Using mice for example you can have the same environment for all mice and the only difference would be the Zika infection. But so far no mouse model for Zika infection is available.

Both strategies are currently worked on and time will tell us the result.

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