Sunday, February 28, 2016

French Polynesia, 2014: how strong is the evidence for Zika-associated microcephaly?

The issue
The 5 February 2016 WHO Situation Report for Zika virus infections reports:

"In light of the increased incidence of microcephaly reported in Brazil, a review of birth data by authorities in French Polynesia indicated an increase in the number of central nervous system malformations in children born between March 2014 and May 2015. 18 cases were reported including 9 microcephaly cases compared to the national average of 0 to 2 cases of microcephaly per year." [1].

Does this represent an increase in proportion of live births with microcephaly at standard levels of statistical significance?

Using the birth rate and population in FP, let's compare 9 cases of microcephaly in 14 months to 0-2 in an 'average' year (with about 4,332 births per annum) [2].

In this plot, the range of microcephaly cases reported annually in 'average' prior years is on the x-axis, and the p-value for a difference in reported proportions with microcephaly is on the y. If we assume zero cases, p= 0.006; if one case, then p for a difference is 0.022; for two cases it's 0.063; and then if we include three cases for completeness, p=0.14. 

US rates are 2 to 12 per 10,000 live births [3]; if comparable to French Polynesia, we'd expect to see ~ 1-6 microcephaly cases in these 5,054 births (14 months). Three cases has a 95% CI of 1-9 cases, and the top end of this range of 6 cases has a 95% CI of 2-13 cases.

Looking at this comparison to US rates another way:

In this plot, up to a rate of 8 cases per 10,000 live births (p=0.014), there is evidence for elevated rates in French Polynesia; at 9 and 10 it's marginal, and above that there's no evidence for differences in rates between the US and FP post-Zika.

There is weak to no evidence to support the statement that there is an increase in microcephaly in French Polynesia post-Zika emergence. With zero cases, there is a statistically significant difference; with a single case it's just scraping significance. Zero cases is improbable as head size is a continuum; and vastly different rates have been captured in Brazil depending on the criteria used [4]; and there is no indication of criteria for these microcephaly cases In FP. Moreover, standardized head measurements have been shown to be inaccurate and may lead to misdiagnoses [5]. Finally, the number of cases reported are within the confidence intervals for rates in the US.

With a total of 8,750 suspect Zika infections [1] amongst a total population of ~278,000 in French Polynesia, I'd expect to see a *much* more robust signal than this if Zika (or Zika in isolation) was causal. However, only 383 (4.4%) of these cases were confirmed, so it's difficult to conclude too much.

Limitations and caveats
This is an inherently crude and 'dirty' analysis. These are very small numbers, of a poorly defined clinical finding subject to many types of reporting biases. These calculations do not use standardized rates (ie, there's no adjustment for age differences in the maternal populations). Finally, reporting of '0-2' in an average year is a very ambiguous statement- if data for actual annual cases were available, this (very simplistic analysis) could be greatly improved.


Analysis in Stata 14 (College Station, TX), using -prtest- to compare the proportions of infants born with microcephaly between birth cohorts.