Another Schizophrenia Twin Study That Only Looks Good When You Skim The Results

 In medical school, my Psychiatry Residency, and even the Psychiatry Board Exams, the concordance rate noted for Schizophrenia was 50%. The assumption here is that if one identical twin was diagnosed with schizophrenia, then the other one had a 50% chance of also being diagnosed with schizophrenia (I am told this is still the conventional wisdom). This is an impressive number, even if it doesn't explain why the other 50%, also genetically identical to their schizophrenic sibling is not also diagnosed with schizophrenia. Well, it appears this is far from accurate, as I've discovered when looking at the actual studies, which we admittedly rarely did in our training, as we filled our heads with the "facts" we needed to pass our training and board certification. It appears to be a bit of statistical sleight of hand. [Hat tip to Jay Joseph (blog linked in my blog roll) for looking at this study a bit past the abstract]:

Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register

If one peruses the abstract of this study, you are met with this:

The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. We estimated the heritability of SZ to be 79%. 

Does that mean that if your identical twin has schizophrenia, you have a 33% chance of having schizophrenia? No, I don't think it does. Does it mean that you have a 79% chance with that stated heritability? No, it doesn't, either.

In fact, based on this study, if one identical twin is diagnosed with schizophrenia, the other was diagnosed with schizophrenia only 14.8% of the time. While that's higher than you would expect at random, it is a far cry from what you might think if you skim the study and feels a bit deceptive, really. So let's see where they come up with their figures.

 Lets first look at the table they present:

We are looking at SCZ (SCZ+ is what they are referrring to as schizophrenia spectrum, a broader diagnosis that I might address later). So of 81 Monozygotic twin pairs where at least one was diagnosed with schizophrenia, 12 had both been diagnosed as schizophrenia, for 14.8% concordance (12/81). Dizygotic twins was 3.2%. This is similar to the concordance in a Finnish study I looked at recently, as well, so it's not really an outlier. So let's look again at their stated concordance:

The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. 

Okay,  I was a bit confused by this. Where do they come up with 33%? So I looked up "probandwise concordance rate" and discovered that this is a different way of calculating the concordance rate and what I'm doing is called the "pairwise concordance rate." (which was used in the Finnish study I noted above). Hmm. Just happens to give a higher number. So I looked to find out why they would use use probandwise instead of pairwise and what the difference is and ran into this little gem of a study:

When assessing twin concordance, use the probandwise not the pairwise rate

Well, maybe "suggestion" is a better description than study. Interestingly, they go right to the heart of it for schizophrenia:

In a recent review of schizophrenia twin studies, however, Torrey (1992) chose to analyze pairwise rather than probandwise rates. Torrey's use of pairwise rates led him to conclude that the monozygotic twin concordance for schizophrenia is weaker than what is widely accepted, and that, by implication, the magnitude of the genetic contribution to schizophrenia has been overestimated. In this brief commentary, we review the relative strengths and weaknesses of the pairwise and probandwise rates and show that Torrey's conclusion is based upon his incorrect use of pairwise rates. Twin studies of schizophrenia continue to support the existence of a strong genetic influence on the development of schizophrenia.

A skeptic might read this and think that probandwise just gives a higher number and makes things look more genetic. A skeptic might also think that the reasoning here is a bit circular. Well, I'm a skeptic. This stuff is not easy to ferret out and there is a lot of debate about it, but reading it over, it appears that a probandwise concordance makes an assumption  that the diagnosis is made without regard to whether the other twin is being diagnosed as schizophrenic. I will cite this paper by Kendler and welcome any correction of misinterpretation.

 In other words, the proband method assumes an absence of two potential sources of biased ascertainment: concordance-dependent ascertainment - in which the probability of becoming a proband differs in affected members of concordant and discordant pairs - and non-independent (or, as termed by some authors, correlated) ascertainment - in which the probability of becoming a proband in a concordant pair depends on the ascertainment status of the affected cotwin. 

If I am understanding that correctly, the idea that a twin that receives a diagnosis of schizophrenia is not going to influence the other twin being diagnosed with schizophrenia is beyond dubious. One of the first things psychiatrists are taught is to take a family history and anytime close family members are noted to have received a particular diagnosis, that influences the psychiatrist and most of all identical twins. Therefore, I take issue with using this method and believe it inflates the concordance. Moreover, even the 14.8% "pairwise" concordance is most certainly inflated for the reasons already cited. I don't think it's a stretch to say that this bias could give the disparity we are seeing between monozygotic and dizygotic concordance rates. This disparity is what creates and, likely inflates the heritability, as well. 

Next let's look at the calculated heritabilty given as 79% as derived, as they don't show their work and even if you accept their concordance calculation, I come up with 52% (2 X (.33 -.07) X 100) [Addendum: I’m told I am using the wrong formula: “shouldn’t it be (rho_MZ - rho_DZ)/(1 - rho_DZ) instead? What you used looked like the Faconer's formula, using corr. coefficients. Still, using the values in the table this gives 27%” So even more confusing. He also noted that the probandwise concordance is inflated and should be 26%. Thanks, KL]. In any case it might strike some as odd that such low concordance rates are coming up with high heritability rates. The reason for this is the disparity in the number of MZ vs DZ pairs concordant for schizophrenia. 

Thus, if we peel away any assumptions about what this means, the high heritability means simply that identical twin pairs are a lot more likely to both be diagnosed with schizophrenia than dizygotic twin pairs. There can be a number of reasons for this, however, so I would take such heritability estimates with a bit of a grain of salt. In fact, going back to that Finnish study from 1984, which had similar concordance figures, I'd highlight this interesting fact:

Of the MZ pairs concordant for psychiatric hospitalization, 47% had lived together for their whole life time; of those discordant, 16% lived together. The corresponding figures for DZ pairs were 18% and 15%.

Thus, when comparing MZ and DZ twins, this indicates that there is a big difference in the way MZ and DZ twins are raised, which is an assumption of twin studies. Clearly, twins living together are more likely to be given a concordant diagnosis. So combining that with the fact that identical twins are probably more likely to be given the same diagnosis, and you have a lot of room for bias, especially when clinicians are led to believe (from studies like this!) that there are higher concordance rates between identical twins vs. fraternal twins. So the fact of the matter is that only 14.8% of the time were both identical twins diagnosed with schizophrenia and it is not out of the question to say that this might be due largely to bias in diagnosing both identical twins the same way.