Explore the vast range of titles available.

This article argues that researchers do not need to completely abandon the p-value, the best-known significance index, but should instead stop using significance levels that do not depend on sample sizes. A testing procedure is developed using a mixture of frequentist and Bayesian tools, with a significance level that is a function of sample size, obtained from a generalized form of the Neyman-Pearson Lemma that minimizes a linear combination of α, the probability of rejecting a true null hypothesis, and β, the probability of failing to reject a false null, instead of fixing α and minimizing β. The resulting hypothesis tests do not violate the Likelihood Principle and do not require any constraints on the dimensionalities of the sample space and parameter space. The procedure includes an ordering of the entire sample space and uses predictive probability (density) functions, allowing for testing of both simple and compound hypotheses. Accessible examples are presented to highlight specific characteristics of the new tests.

Population genetic tools can facilitate successful conservation and management of wildlife populations. However, the ability of such approaches to inform wildlife management and conservation programs depends upon assumptions linking genetic patterns to ecological processes, one implicit assumption usually being that genetic parameters (e.g., population genetic differentiation) estimated using a set of loci accurately reflect underlying demographic and microevolutionary forces affecting the population(s) under study. This is an important assumption because it also implies that we have acknowledged that genetic parameters estimated by a set of target loci inherently are associated with a sampling variance. Specifically, a perception exists that heterozygote deficits caused by biological mechanisms (e.g., a Wahlund effect) and null alleles can be differentiated by the expectation that the former leads to a concordant pattern across all loci, whereas the latter leads to locus-specific effects. We use Monte-Carlo simulation to demonstrate that these expectations do not always hold under biologically realistic conditions. Our analyses indicate that the conservative approach of discarding loci deviating from Hardy-Weinberg equilibrium expectations could rob us of our most informative markers, weakening our ability to interpret biological phenomena.

Retrospective analyses conducted within the prospective Breast International Group 1-98 (BIG 1-98) (6) and the Anastrozole, Tamoxifen, Alone or in Combination (ATAC)trials (7) failed to validate an association between CYP2D6 genotype and clinical outcomes in breast cancer patients receiving tamoxifen in the adjuvant setting. [...]significant deviations from HWE for CYP2D6*4 are common in studies that genotype germline DNA (11,12), including a study from Bijl et al. that had a substantial HWE deviation (p=3×10-13) (13). [...]of the 23 discordant genotype calls, five (22%) were homozygous for one allele in the benign tissue DNA but heterozygous (n=2) or homozygous for the other allele (n=3) in the tumor-derived DNA (10). Since LOH would not introduce nonexistent alleles into the tumor DNA, these discordant calls could not have been caused by LOH. CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients: a meta-analysis.

Traditionally population genetics precludes the use of the same genetic individual more than once in Hardy–Weinberg (HW) based calculations due to the model's explicit assumptions. However, when applied to clonal plant populations this can be difficult to do, and in some circumstances, it may be ecologically informative to use the ramet as the data unit. In fact, ecologists have varied the definition of the individual from a strict adherence to a single data point per genotype to a more inclusive approach of one data point per ramet. With the advent of molecular tools, the list of facultatively clonal plants and the recognition of their ecological relevance grows. There is an important risk of misinterpretation when HW calculations are applied to a clonal plant not recognized as clonal, as well as when the definition of the individual for those calculations is not clearly stated in a known clonal species. Focusing on heterozygosity values, we investigate cases that demonstrate the extreme range of potential modeling outcomes and describe the different contexts where a particular definition could better meet ecological modeling goals. We emphasize that the HW model can be ecologically relevant when applied to clonal plants, but caution is necessary in how it is used, reported, and interpreted. We propose that in known clonal plants, both genotype (GHet) and ramet (RHet) based calculations are reported to define the full range of potential values and better facilitate cross‐study comparisons. There is an important risk of misinterpretation when HW calculations are applied to a clonal plant not recognized as clonal, as well as when the definition of the individual for those calculations is not clearly stated in a known clonal species. Focusing on heterozygosity values we investigate cases that demonstrate the extreme range of potential modeling outcomes and describe the different contexts where a particular definition could better meet ecological modeling goals. We emphasize that the HW model can be ecologically relevant when applied to clonal plants, but caution is necessary in how it is used, reported and interpreted.

The Hardy–Weinberg (HW) principle explains how random mating (RM) can produce and maintain a population in equilibrium, that is, with constant genotypic proportions. When proportions diverge from HW form, it is of interest to estimate the fixation index F, which reflects the degree of divergence. Starting from a sample of genotypic counts, a mixed procedure gives first the orthodox estimate of gene frequency q and then a Bayesian estimate of F, based on a credible prior distribution of F, which is described here.

Congenital heart disease (CHD) is a complex illness with high rates of morbidity and mortality. In embryonic development, the heart is the first formed organ, which is strictly controlled by gene regulatory networks, including transcription factors, signaling pathways, epigenetic factors and microRNAs. Bone morphogenetic protein (BMP)-2 and -4 are essential in cardiogenesis as they can induce the expression of transcription factors, NKX2-5 and GATA binding protein 4, which are important in the development of the heart. The inhibition of BMP-2 and 4- inhibits the late expression of NKX2-5 and affects cardiac differentiation. The aim of the present study was to investigate whether BMP-2 and -4 variations may be associated with CHD in Chinese Han populations. The rs1049007, rs235768 and rs17563 single nucleotide polymorphisms (SNPs), which are genetic variations located within the translated region of the BMP-2 and -4, were evaluated in 230 patients with CHD from the Chinese Han population and 160 non CHD control individuals. Statistical analyses were performed using the χ2 test, implemented using SPSS software (version 13.0). The Hardy Weinberg equilibrium test was performed on the population using online Online Encyclopedia for Genetic Epidemiology studies software, and multiple-sequence alignments of the BMP proteins were performed using Vector NTI software. No statistically significant associations were identified between these genetic variations and the risk of CHD (rs1049007, P value=0.560; rs235768, P value=0.972; rs17563, P value=0.787). In addition, no correlation was found between the patients with CHD and the non-CHD control individuals. Therefore, the rs1049007, rs235768 and rs17563 genetic variations of BMP-2 were not associated with CHD in the Chinese Han population.

Background: Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine that may act as an endogenous tumor promoter. A genetic polymorphism of TNF-α gene at position −308 promoter region is involved in the regulation of expression level and has been found to be associated with susceptibility to various types of cancer. Methods: To determine the association of the TNF-α gene G-308A polymorphism on the risk of hepatocellular carcinoma (HCC) in a Turkish population, a hospital-based case-control study was designed consisting of 110 diagnosis subjects with hepatocellular carcinoma and 110 cancer-free control subjects matched on age, gender, smoking and alcohol status. The genotype frequency of this polymorphism was determined by using a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay. Results: The distribution G-308A genotype was significantly associated with the risk of HCC ( p < 0.001, odds ratio [OR] = 4.75, 95% confidence interval [CI] = 2.25–9.82 for −308 AA/GA genotypes versus GG genotype). Conclusion: We suggested that the presence of the high producer allele −308A in the TNF-α gene appears to be associated with an increased risk for the development of HCC in Turkish population.

Background An alternative approach to investigate associations between genetic variants and disease is to examine deviations from the Hardy–Weinberg equilibrium (HWE) in genotype frequencies within a case population, instead of case–control association analysis. The HWE analysis requires disease cases and demonstrates a notable ability in mapping recessive variants. Allelic heterogeneity is a common phenomenon in diseases. While gene-based case–control association analysis successfully incorporates this heterogeneity, there are no such approaches for HWE analysis. Therefore, we proposed a gene-based HWE test (gene-HWT) by aggregating single-nucleotide polymorphism (SNP)-level HWE test statistics in a gene to address allelic heterogeneity. Results This method used only genotype count data and publicly available linkage disequilibrium information and has a very low computational cost. Extensive simulations demonstrated that gene-HWT effectively controls the type I error at a low significance level and outperforms SNP-level HWE test in power when there are multiple causal variants within a gene. Using gene-HWT, we analyzed genotype count data from a genome-wide association study of six cancer types in Japanese individuals and suggest DGKE and ANO3 as potential germline factors in colorectal cancer. Furthermore, FSTL4 was suggested through a combined analysis across the six cancer types, with particularly notable associations observed in colorectal and prostate cancers. Conclusions These findings indicate the potential of gene-HWT to elucidate the genetic basis of complex diseases, including cancer.

The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity. Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I(2) statistics and publication bias using Egger's test and Begg and Mazumdar's test. Individual participant data obtained from five studies were used for subgroup analyses. Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24-1.69) and 2.22 (1.50-3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79-2.44) and 3.37 (2.49-4.58) and among AC patients with HCC was 2.87 (1.61-5.10) and 12.41 (6.99-22.03). Data for AFL were inconsistent. Among ALD patients, OR of CG and GG genotypes was 2.62 (1.73-3.97) and 8.45 (2.52-28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24-3.17) and 3.86 (1.18-12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76-2.72) and 2.81 (1.57-5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients. PNPLA3 genetic polymorphism (rs738409 C>G) is associated with increased risk for the entire spectrum of ALD among drinkers including ALI, AC, and HCC. Studies are needed to clarify association of PNPLA3 polymorphism and steatosis in alcoholics. PNPLA3 gene may potentially be a therapeutic target in ALD.

Background: Recent work suggests that multiple genes and several environmental risk factors influence risk for non-syndromic oral clefts, one of the most common birth defects in humans. Advances in high-throughput genotyping technology now make it possible to test multiple markers in many candidate genes simultaneously. Methods: We present findings from family based association tests of single nucleotide polymorphism (SNP) markers in 64 candidate genes genotyped using the BeadArray approach in 58 case-parent trios from Maryland (USA) to illustrate how multiple markers in multiple genes can be analysed. To assess whether these genes were expressed in human craniofacial structures relevant to palate and lip development, we also analysed data from the Craniofacial and Oral Gene Expression Network (COGENE) consortium, and searched public databases for expression profiles of these genes. Results: Thirteen candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were found to be expressed in relevant embryonic tissues: SP100, MLPH, HDAC4, LEF1, C6orf105, CD44, ALX4, ZNF202, CRHR1, and MAPT. Three other genes showing statistical evidence (ADH1C, SCN3B, and IMP5) were not expressed in the embryonic tissues examined here. Conclusions: This approach demonstrates how statistical evidence on large numbers of SNP markers typed in case-parent trios can be combined with expression data to identify candidate genes for complex disorders. Many of the genes reported here have not been previously studied as candidates for oral clefts and warrant further investigation.