Behavioural Genetic Interactive Modules

Extremes Analysis

Overview

This module aims to introduce the concept of DF group analysis.

Introduction to DeFries-Fulker Extremes Analysis

DeFries-Fulker analysis (DF analysis) is a regression-based method for the analysis of twin data. It was designed particularly for the case of proband-ascertained samples: an example of a non-random sample. This approach ascertains extreme scoring individuals (probands) along with their co-twin. This means that in every twin pair, at least one of the twins will be a high scorer. As a result, standard correlational and model-fitting methods of analysis are no longer entirely appropriate.

DF analysis is based on the principle of regression to the mean. To illustrate this, consider the following example:

Imagine that we have 1000 individuals and test them on some measure, such as the amount of exercise they had done in the last week. We might expect the following type of frequency distribution chart, where some individuals do lots (at the right-hand-side of the plot), some do none (at the left-hand-side), but most do an intermediate amount (in the middle).

If we were to re-test the same individuals a month later, what would we expect the plot to look like? We have no reason to believe the mean or variance of the distribution should have changed at all: on average, nothing special should have happened to our sample in their exercise habits. We would expect exactly the same pattern :

However, what if we focused on the group of individuals who scored very low at the first measurement occasion:

Is there any way of predicting what will happen to the mean of this group at the second measurement occasion?

The mean at the second occasion of the group who were extreme at the first occasion will depend on the underlying correlation between the two occasions.

Imagine the correlation was +1. All individuals would have exactly the same score at the second time as they had for the first time. The implication of this is that the extreme group would continue to be equally extreme at the second occasion.

Imagine the correlation was 0. An individual's score at the second time point would be unrelated to their score at the first. The implication of this is that the mean of the extreme group should regress back to the mean on the second occasion.

And for intermediate correlations, individuals who score low the first time are more likely to also score low at the second time. The implication of this is that the mean of the extreme group would be expected to partially regress towards the mean at the second occasion.

In this manner, studying the extent of regression to the mean over two points can be used as a tool for estimating the correlation between those two measures. In this sense, we are observing means to say something about the variance/covariance of the measures. (cf. ANOVA, which observes variances in order to say something about mean differences).

DF analysis takes advantage of the ability to extract information about the correlation between two measure by studying the regression to the mean. We are not concerned here with measurements at two time points in the same individual: we are interested in the correlation between twins. In this context, the two measurements are the scores of each twin. The equivalent of the extreme group at time one are all the probands; the second measurement occasion is equivalent to their co-twin's score.

If a trait is genetic, we should expect differential regression to the mean between MZ and DZ co-twins of extreme probands. As the extent of regression to the mean represents the correlation between twins, this is equivalent to asking whether or not the trait is more correlated amongst MZ than DZ twins: i.e. the fundamental basis of quantitative genetic analysis.

Because the regression to the mean essentially reflects information about the correlation between twins, if the means are appropriately standardised so that the population mean becomes 0 and the proband mean becomes 1, then the transformed MZ and DZ co-twin means can be interpreted in exactly the same manner as MZ and DZ correlations can be.

That is, twice the difference between MZ and DZ co-twin mean estimates the heritability, 1 minus the MZ co-twin mean represents the effect of nonshared environment. Represented graphically:

The standardisation procedure is very simple : we have four means, that we should expect to find in this order:
• Population mean
• DZ co-twin mean
• MZ co-twin mean
• Proband mean
If we a) subtract the population mean from each of the four means, and then divide each of the results by this new proband mean, this will ensure the transformed population mean is zero, the proband mean will be 1, and the MZ and DZ co-twin means should be somewhere in between.

The Module

The module simulates a population of 20,000 individuals (5000 MZ pairs and 5000 DZ pairs) according to the population parameters specified in the panel, as shown to the right. As well as using the sliders to determine the relative balance of additive genetic, shared environmental and nonshared environmental variance for this trait (A, C and E), we also have to specify a threshold that will be used to select probands.

The module simulates a trait that ranges between 1 and 20: the threshold is expressed in the raw-units of the trait. All individuals scoring at the threshold or lower become probands. Here we see the distribution of the all individuals' scores. That is, both twins in a pair are plotted and so both can become probands if their scores are both below threshold. Both twins will also be co-twins in this case. This is called double-entry and has to be statistically corrected for when estimating the significance of a DF result (as some individuals are essentially counted twice) but it does not affect the ideas we are dealing with here in any way.

The little white and red dots on the axis represent the population and proband means respectively.

After simulating the twin population, the module selects the co-twins of probands and plots their scores, separately for MZ and DZ co-twins. The co-twin means are also calculated and plotted on the axes, also. Here is the MZ co-twin distribution.

And here is the DZ co-twin distribution.

As can be seen from these graphs, the DZ co-twins score higher on average than the MZ co-twins. This represents the differential regression to the mean between MZ and DZ co-twins, that reflects the difference in correlations between MZ and DZ co-twins.

These means are summarised in the panel, shown to the right. As expected, the proband mean is the lowest, the MZ co-twin mean the next lowest, the DZ co-twin mean next and the population mean last.

If we transform these means in the manner described above we arrive at the DF analysis estimates for A, C and E. This panel also tells you what percentage of the population were selected as probands for the specific threshold used.

The DF analysis has done a good job here. In this instance, the data were simulated under:
• A = 73%
• C = 20%
• E = 7%
We see that the estimates derived from DF analysis are incredibly similar, as we should hope! (it is only rounding error which makes the total variance 101% here)
• A = 70%
• C = 23%
• E = 8%
We should have expected this because the sample size was so large (20,000 individuals, 14% of which were probands). If our sample had only contained the probands and their co-twins, however, the standard model-fitting results would have been much harder to derive: DF analysis would have been uniquely useful in that context.

Exploring the module

Try experimenting with different thresholds and different values for A, C and E in order to see how the MZ and DZ co-twin means reflect these components of variance. For example, notice however both co-twin means regress back to near the population mean when then trait is predominantly determined by nonshared environmental sources of variation.

Regression model

Typically DF analysis is performed within a linear regression model. The heart of it is embodied above, however: the comparison of co-twin means. The regression estimates the same quantities but also allows for confidence intervals to be put around the estimates in a very straight-forward manner, using standard statistical packages such as SPSS. See the Appendix and Box 8.1 of the Behavioral Genetics text for further explanation of DF analysis.

Heterogeneous Populations

But what if DF analysis of extreme probands and their co-twins gives significantly different results to standard ACE analyses for the same trait in similar populations? In this simulation we know that we have simulated a homogeneous population, so the DF estimates should always mirror the population parameters, give or take sampling error. The population is homogeneous in the sense that the population parameters describe the sample equally well at any point along the distribution. It might be that there is 'something special' about the individuals with extreme scores that might represent a different aetiology compared to the unselected population acting in these individuals, however. In this case, we might expect DF analysis to reflect this difference, relative to analysis of variation in the trait throughout the normal range. Such 'special' factors might include rare genes of major effect, certain strong epistatic or gene by environmental effects, or admixed populations. Such factors might imply that the causes of disability, for example, (as indexed by proband status) are quantitatively or qualitatively different from the causes of normal variation (as indexed by standard analysis of individual differences).

Site created by S.Purcell, last updated 13.11.2000