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.Peer reviewe

Computational issues in parameter estimation for hidden Markov models with Template Model Builder

A popular way to estimate the parameters of a hidden Markov model (HMM) is direct numerical maximization (DNM) of the (log-)likelihood function. The advantages of employing the TMB (Kristensen et al., 2016) framework in R for this purpose were illustrated recently Bacri et al. (2022). In this paper, we present extensions of these results in two directions. First, we present a practical way to obtain uncertainty estimates in form of confidence intervals (CIs) for the so-called smoothing probabilities at moderate computational and programming effort via TMB. Our approach thus permits to avoid computer-intensive bootstrap methods. By means of several examples, we illustrate patterns present for the derived CIs. Secondly, we investigate the performance of popular optimizers available in R when estimating HMMs via DNM. Hereby, our focus lies on the potential benefits of employing TMB. Investigated criteria via a number of simulation studies are convergence speed, accuracy, and the impact of (poor) initial values. Our findings suggest that all optimizers considered benefit in terms of speed from using the gradient supplied by TMB. When supplying both gradient and Hessian from TMB, the number of iterations reduces, suggesting a more efficient convergence to the maximum of the log-likelihood. Last, we briefly point out potential advantages of a hybrid approach.Comment: 20 pages without appendix, 33 pages with appendix, 15 figures, 5 table