Nonparametric Evaluation of Quantitative Traits in Population-Based Association Studies when the Genetic Model is Unknown

Statistical association between a single nucleotide polymorphism (SNP) genotype and a quantitative trait in genome-wide association studies is usually assessed using a linear regression model, or, in the case of non-normally distributed trait values, using the Kruskal-Wallis test. While linear regression models assume an additive mode of inheritance via equi-distant genotype scores, Kruskal-Wallis test merely tests global differences in trait values associated with the three genotype groups. Both approaches thus exhibit suboptimal power when the underlying inheritance mode is dominant or recessive. Furthermore, these tests do not perform well in the common situations when only a few trait values are available in a rare genotype category (disbalance), or when the values associated with the three genotype categories exhibit unequal variance (variance heterogeneity). We propose a maximum test based on Marcus-type multiple contrast test for relative effect sizes. This test allows model-specific testing of either dominant, additive or recessive mode of inheritance, and it is robust against variance heterogeneity. We show how to obtain mode-specific simultaneous confidence intervals for the relative effect sizes to aid in interpreting the biological relevance of the results. Further, we discuss the use of a related all-pairwise comparisons contrast test with range preserving confidence intervals as an alternative to Kruskal-Wallis heterogeneity test. We applied the proposed maximum test to the Bogalusa Heart Study dataset, and gained a remarkable increase in the power to detect association, particularly for rare genotypes. Our simulation study also demonstrated that the proposed non-parametric tests control family-wise error rate in the presence of non-normality and variance heterogeneity contrary to the standard parametric approaches. We provide a publicly available R library nparcomp that can be used to estimate simultaneous confidence intervals or compatible multiplicity-adjusted p-values associated with the proposed maximum test.

Regional differences of outpatient physician supply as a theoretical economic and empirical generalized linear model

BACKGROUND: Regional differences in physician supply can be found in many health care systems, regardless of their organizational and financial structure. A theoretical model is developed for the physicians' decision on office allocation, covering demand-side factors and a consumption time function. METHODS: To test the propositions following the theoretical model, generalized linear models were estimated to explain differences in 412 German districts. Various factors found in the literature were included to control for physicians' regional preferences. RESULTS: Evidence in favor of the first three propositions of the theoretical model could be found. Specialists show a stronger association to higher populated districts than GPs. Although indicators for regional preferences are significantly correlated with physician density, their coefficients are not as high as population density. CONCLUSIONS: If regional disparities should be addressed by political actions, the focus should be to counteract those parameters representing physicians' preferences in over- and undersupplied regions.