Testing allele homogeneity: the problem of nested hypotheses

Background: The evaluation of associations between genotypes and diseases in a case-control framework plays an important role in genetic epidemiology. This paper focuses on the evaluation of the homogeneity of both genotypic and allelic frequencies. The traditional test that is used to check allelic homogeneity is known to be valid only under Hardy-Weinberg equilibrium, a property that may not hold in practice. Results: We first describe the flaws of the traditional (chi-squared) tests for both allelic and genotypic homogeneity. Besides the known problem of the allelic procedure, we show that whenever these tests are used, an incoherence may arise: sometimes the genotypic homogeneity hypothesis is not rejected, but the allelic hypothesis is. As we argue, this is logically impossible. Some methods that were recently proposed implicitly rely on the idea that this does not happen. In an attempt to correct this incoherence, we describe an alternative frequentist approach that is appropriate even when Hardy-Weinberg equilibrium does not hold. It is then shown that the problem remains and is intrinsic of frequentist procedures. Finally, we introduce the Full Bayesian Significance Test to test both hypotheses and prove that the incoherence cannot happen with these new tests. To illustrate this, all five tests are applied to real and simulated datasets. Using the celebrated power analysis, we show that the Bayesian method is comparable to the frequentist one and has the advantage of being coherent. Conclusions: Contrary to more traditional approaches, the Full Bayesian Significance Test for association studies provides a simple, coherent and powerful tool for detecting associations.

Assessing the extent of colon lengthening due to splenic flexure mobilization techniques: a cadaver study

CONTEXT: Failure of a colorectal anastomosis represents a life-threatening complication of colorectal surgery. Splenic flexure mobilization may contribute to reduce the occurrence of anastomotic complications due to technical flaws. There are no published reports measuring the impact of splenic flexure mobilization on the length of mobilized colon viable to construct a safe colorectal anastomosis. OBJECTIVE: The aim of the present study was to determine the effect of two techniques for splenic flexure mobilization on colon lengthening during open left-sided colon surgery using a cadaver model. DESIGN: Anatomical dissections for left colectomy and colorectal anastomosis at the sacral promontory level were conducted in 20 fresh cadavers by the same team of four surgeons. The effect of partial and full splenic flexure mobilization on the extent of mobilized left colon segment was determined. SETTING: University of Sao Paulo Medical School, Sao Paulo, SP, Brazil. Tertiary medical institution and university hospital. PARTICIPANTS: A team of four surgeons operated on 20 fresh cadavers. RESULTS: The length of resected left colon enabling a tension-free colorectal anastomosis at the level of sacral promontory achieved without mobilizing the splenic flexure was 46.3 (35-81) cm. After partial mobilization of the splenic flexure, an additionally mobilized colon segment measuring 10.7 (2-30) cm was obtained. After full mobilization of the distal transverse colon, a mean 28.3 (10-65) cm segment was achieved. CONCLUSION: Splenic flexure mobilization techniques are associated to effective left colon lengthening for colorectal anastomosis. This result may contribute to decision-making during rectal surgery and low colorectal and coloanal anastomosis.