The heritability of BMI varies across the range of BMI-a heritability curve analysis in a twin cohort.

BACKGROUND: The heritability of traits such as body mass index (BMI), a measure of obesity, is generally estimated using family and twin studies, and increasingly by molecular genetic approaches. These studies generally assume that genetic effects are uniform across all trait values, yet there is emerging evidence that this may not always be the case. METHOD/SUBJECTS: This paper analyzes twin data using a recently developed measure of heritability called the heritability curve. Under the assumption that trait values in twin pairs are governed by a flexible Gaussian mixture distribution, heritability curves may vary across trait values. The data consist of repeated measures of BMI on 1506 monozygotic (MZ) and 2843 like-sexed dizygotic (DZ) adult twin pairs, gathered from multiple surveys in older Finnish Twin Cohorts. RESULTS: The heritability curve and BMI value-specific MZ and DZ pairwise correlations were estimated, and these varied across the range of BMI. MZ correlations were highest at BMI values from 21 to 24, with a stronger decrease for women than for men at higher values. Models with additive and dominance effects fit best at low and high BMI values, while models with additive genetic and common environmental effects fit best in the normal range of BMI. CONCLUSIONS: We demonstrate that twin and molecular genetic studies need to consider how genetic effects vary across trait values. Such variation may reconcile findings of traits with high heritability and major differences in mean values between countries or over time.

A gentle tutorial on accelerated parameter and confidence interval estimation for hidden Markov models using Template Model Builder.

A very common way to estimate the parameters of a hidden Markov model (HMM) is the relatively straightforward computation of maximum likelihood (ML) estimates. For this task, most users rely on user-friendly implementation of the estimation routines via an interpreted programming language such as the statistical software environment R. Such an approach can easily require time-consuming computations, in particular for longer sequences of observations. In addition, selecting a suitable approach for deriving confidence intervals for the estimated parameters is not entirely obvious, and often the computationally intensive bootstrap methods have to be applied. In this tutorial, we illustrate how to speed up the computation of ML estimates significantly via the R package TMB. Moreover, this approach permits simple retrieval of standard errors at the same time. We illustrate the performance of our routines using different data sets: first, two smaller samples from a mobile application for tinnitus patients and a well-known data set of fetal lamb movements with 87 and 240 data points, respectively. Second, we rely on larger data sets of simulated data of sizes 2000 and 5000 for further analysis. This tutorial is accompanied by a collection of scripts, which are all available in the Supporting Information. These scripts allow any user with moderate programming experience to benefit quickly from the computational advantages of TMB.

Heritability curves: A local measure of heritability in family models.

Classical heritability models for family data split the phenotype variance into genetic and environmental components. For instance, the ACE model in twin studies assumes the phenotype variance decomposes as a2 + c2 + e2 , representing (additive) genetic effects, common (shared) environment, and residual environment, respectively. However, for some phenotypes it is biologically plausible that the genetic and environmental components may vary over the range of the phenotype. For instance, very large or small values of the phenotype may be caused by "sporadic" environmental factors, whereas the mid-range phenotype variation may be more under the control of common genetic factors. This article introduces a "local" measure of heritability, where the genetic and environmental components are allowed to depend on the value of the phenotype itself. Our starting point is a general formula for local correlation between two random variables. For estimation purposes, we use a multivariate Gaussian mixture, which is able to capture nonlinear dependence and respects certain distributional constraints. We derive an analytical expression for the associated correlation curve, and show how to decompose the correlation curve into genetic and environmental parts, for instance, a2 (y) + c2 (y) + e2 (y) for the ACE model, where we estimate the components as functions of the phenotype y. Furthermore, our model allows switching, for instance, from the ACE model to the ADE model within the range of the same phenotype. When applied to birth weight (BW) data on Norwegian mother-father-child trios, we conclude from the model that low and high BW are less heritable traits than medium BW. We also demonstrate switching between the ACE and ADE model when studying body mass index in adult monozygotic and dizygotic twins.

Variation in use of Caesarean section in Norway: An application of spatio-temporal Gaussian random fields.

AIMS: Caesarean section (CS) is a medical intervention performed in Norway when a surgical delivery is considered more beneficial than a vaginal. Because deliveries with higher risk are centralized to larger hospitals, use of CS varies considerably between hospitals. We describe how the use of CS varies geographically by municipality. Since indications for CS should have little variation across the relatively homogenous population of Norway, we expect fair use of CS to be evenly distributed across the municipalities. METHODS: Data from the Medical Birth Registry of Norway were used in our analyses (810,914 total deliveries, 133,746 CSs, 440 municipalities). We propose a spatial correlation model that takes the location into account to describe the variation in use of CS across the municipalities. The R packages R-INLA and TMB are used to estimate the yearly municipal CS rate and the spatial correlation between the municipalities. We also apply stratified models for different categories of delivering women (Robson groups). Estimated rates are displayed in maps and model parameters are shown in tables. RESULTS: The CS rate varies substantially between the different municipalities. As expected, there was strong correlation between neighbouring municipalities. Similar results were found for different Robson groups. CONCLUSIONS: The substantial difference in CS use across municipalities in Norway is not likely to be due to specific medical reasons, but rather to hospitals' different policies towards the use of CS. The policy to be either more or less restrictive to CS was not specific to any category of deliveries.