Epistasis in the multiple locus symmetric viability model

The n-locus two-allele symmetric viability model is considered in terms of the parameters measuring the additive epistasis in fitness. The dynamics is analysed using a simple linear transformation of the gametic frequencies, and then the recurrence equations depend on the epistatic parameters and Geiringer's recombination distribution only. The model exhibits an equilibrium, the central equilibrium, where the 2 ⁿ gametes are equally frequent. The transformation simplifies the stability analysis of the central point, and provides the stability conditions in terms of the existence conditions of other equilibria. For total negative epistasis (all epistatic parameters are negative) the central point is stable for all recombination distributions. For free recombination either a central point (segregating one, two, ... or n loci) or the n-locus fixation states are stable. For no recombination and some epistatic parameters positive the central point is unstable and several boundary equilibria may be locally stable. The sign structure of the additive epistasis is therefore an important determinant of the dynamics of the n-locus symmetric viability model. The non-symmetric multiple locus models previously analysed are dynamically related, and they all have an epistatic sign structure that resembles that of the multiplicative viability model. A non-symmetric model with total negative epistasis which share dynamical properties with the similar symmetric model is suggested.Supported in part by NIH grant GM 28016, and by grant 81-5458 from the Danish Natural Science Research Council     

Putting prey back together again: integrating predator-induced behavior,morphology, and life history

The last decade has seen an explosion in the number of studies exploring predator-induced plasticity. Recently, there has been a call for more comprehensive approaches that can identify functional relationships between traits, constraints on phenotypic responses, and the cost and benefits of alternative phenotypes. In this study, we exposed Helisoma trivolvis, a freshwater snail, to a factorial combination of three resource levels and five predator environments (no predator, one or two water bugs, and one or two crayfish) and examined ten traits including behavior, morphology, and life history. Each predator induced a unique suite of behavioral and morphological responses. Snails increased near-surface habitat use with crayfish but not with water bugs. Further, crayfish induced narrow and high shells whereas water bugs induced wide shells and wide apertures. In terms of life history, both predators induced delayed reproduction and greater mass at reproduction. However, crayfish induced a greater delay in reproduction that resulted in reduced fecundity whereas water bugs did not induce differences in fecundity. Resource levels impacted the morphology of H. trivolvis; snails reared with greater resource levels produced higher shells, narrower shells, and wider apertures. Resource levels also impacted snail life history; lower resources caused longer times to reproduction and reduced fecundity. Based on an analysis of phenotypic correlations, the morphological responses to each predator most likely represent phenotypic trade-offs. Snails could either produce invasion-resistant shells for defense against water bugs or crush-resistant shells for defense against crayfish, but not both. Our use of a comprehensive approach to examine the responses of H. trivolvis has provided important information regarding the complexity of phenotypic responses to different environments, the patterns of phenotypic integration across environments, and the potential costs and benefits associated with plastic traits.     

Obtaining Critical Values for Simultaneous Confidence Intervals and Multiple Testing

There are many situations where it is desired to make simultaneous tests or give simultaneous confidence intervals for linear combinations (contrasts) of population or treatment means. Somerville (1997, 1999) developed algorithms for calculating the critical values for a large class of simultaneous tests and simultaneous confidence intervals. Fortran 90 and SAS‐IML batch programs and interactive programs were developed. These programs calculate the critical values for 15 different simultaneous confidence interval procedures (and the corresponding simultaneous tests) and for arbitrary procedures where the user specifies a combination of one and two sided contrasts. The programs can also be used to obtain the constants for “step‐down” testing of multiple hypotheses. This paper gives examples of the use of the algorithms and programs and illustrates their versatility and generality. The designs need not be balanced, multiple covariates may be present and there may be many missing values. The use of multiple regression and dummy variables to obtain the required variance covariance matrix is illustrated. Under weak normality assumptions the methods are “exact” and make the use of approximate methods or “simulation” unnecessary.     

多发性骨髓瘤遗传学的研究进展

多发性骨髓瘤起源于后生发中心的B细胞,是一种不可治愈的慢性进展性骨髓浆细胞恶性肿瘤,约占血液系统肿瘤的10%。多发性骨髓瘤存在明显的遗传学改变,其早期的遗传学改变是免疫球蛋白重链基因位点的易位,而这些易位常常导致11q13区域的cyclin D1、4p16.3区域的FGFR3/MMSET、16q23区域的c-maf、6p21区域的cyclin D3等癌基因的失调,同时还存在抑癌基因位点13q14的丢失以及13号染色单体的缺失,这些染色体异常与疾病的预后密切相关。并且N-RAS、K-RAS的突变,以及c-Myc改变等继发性的改变和癌基因的活化等也与疾病的进展密切关联。近年来,随着医学技术的不断进步,人们对该病的遗传学改变认识进一步加深。本文对多发性骨髓瘤的遗传学改变研究进展进行综述,旨在为指导临床有效治疗多发性骨髓瘤,有效评估预后提供参考。     

A tail strength measure for assessing the overall univariate significance in a dataset

We propose an overall measure of significance for a set of hypothesis tests. The 'tail strength' is a simple function of the p-values computed for each of the tests. This measure is useful, for example, in assessing the overall univariate strength of a large set of features in microarray and other genomic and biomedical studies. It also has a simple relationship to the false discovery rate of the collection of tests. We derive the asymptotic distribution of the tail strength measure, and illustrate its use on a number of real datasets.     

Controlling the false discovery rate with constraints: the Newman-Keuls test revisited

The Newman-Keuls (NK) procedure for testing all pairwise comparisons among a set of treatment means, introduced by Newman (1939) and in a slightly different form by Keuls (1952) was proposed as a reasonable way to alleviate the inflation of error rates when a large number of means are compared. It was proposed before the concepts of different types of multiple error rates were introduced by Tukey (1952a, b; 1953). Although it was popular in the 1950s and 1960s, once control of the familywise error rate (FWER) was accepted generally as an appropriate criterion in multiple testing, and it was realized that the NK procedure does not control the FWER at the nominal level at which it is performed, the procedure gradually fell out of favor. Recently, a more liberal criterion, control of the false discovery rate (FDR), has been proposed as more appropriate in some situations than FWER control. This paper notes that the NK procedure and a nonparametric extension controls the FWER within any set of homogeneous treatments. It proves that the extended procedure controls the FDR when there are well-separated clusters of homogeneous means and between-cluster test statistics are independent, and extensive simulation provides strong evidence that the original procedure controls the FDR under the same conditions and some dependent conditions when the clusters are not well-separated. Thus, the test has two desirable error-controlling properties, providing a compromise between FDR control with no subgroup FWER control and global FWER control. Yekutieli (2002) developed an FDR-controlling procedure for testing all pairwise differences among means, without any FWER-controlling criteria when there is more than one cluster. The empirica example in Yekutieli's paper was used to compare the Benjamini-Hochberg (1995) method with apparent FDR control in this context, Yekutieli's proposed method with proven FDR control, the Newman-Keuls method that controls FWER within equal clusters with apparent FDR control, and several methods that control FWER globally. The Newman-Keuls is shown to be intermediate in number of rejections to the FWER-controlling methods and the FDR-controlling methods in this example, although it is not always more conservative than the other FDR-controlling methods.     

Simultaneous Comparisons of Multiple Treatments to Two (or More) Control

DUNNETT (1955) developed a procedure simultaneously comparing k treatments to one control with an exact overall type I error of α when all sampling distributions are normal. Sometimes it is desirable to compare k treatments to m≧2 controls, in particular to two controls. For instance, several new therapies (e.g., pain relievers) could be compared to two standard therapies (e.g., Aspirin and Tylenol). Alternatively, a standard therapy could be very expensive, difficult to apply and/or have bad side effects, making it useful to compare each new therapy to both standard therapy and no therapy (Placebo). Dunnett's method is expanded here to give comparisons of mean values for k treatments to mean values for m≧2 controls at an exact overall type I error of α when all sampling distributions are normal. Tabled values needed to make exact simultaneous comparisons at α = .05 are given for m = 2. An application is made to an example from the literature.     

一端受外力的交联振荡器链中的内部传输

本文研究了二类一端受外力的交联振荡器链：最邻近多相位交联振荡器链,以及多重交联振荡器链,讨论了它们产生内部传输,即各振荡器与外力具有相同频率的现象。文中近似相位差方程、指数二分性理论和中心流形理论被应用于系统的渐近近似。研究。本文得到了更符合于实际情况的神经网络CPG链动态特性分析结论。     

Multiple Testing for Identifying Effective and Safe Treatments

In the literature various multiple test procedures to compare k treatments with a control have been investigated. They can be applied to establish either treatment efficacy or treatment safety. In this paper we propose procedures which control the multiple level α with respect to efficacy and safety simultaneously. On the one hand we consider a method with stagewise rejective adjustments of local levels applied to appropriately defined subfamilies of null hypotheses. When order restrictions are assumed to hold among the parameters of interest we can alternatively split the multiple level between the families of efficacy and safety null hypotheses. If either all treatments are declared to be safe or all are declared to be effective then the other family can be tested at the full multiple level α, respectively. The methods are compared in a simulation study.     

MDAT- Aligning multiple domain arrangements

Background

Proteins are composed of domains, protein segments that fold independently from the rest of the protein and have a specific function. During evolution the arrangement of domains can change: domains are gained, lost or their order is rearranged. To facilitate the analysis of these changes we propose the use of multiple domain alignments.

Results

We developed an alignment program, called MDAT, which aligns multiple domain arrangements. MDAT extends earlier programs which perform pairwise alignments of domain arrangements. MDAT uses a domain similarity matrix to score domain pairs and aligns the domain arrangements using a consistency supported progressive alignment method.

Conclusion

MDAT will be useful for analysing changes in domain arrangements within and between protein families and will thus provide valuable insights into the evolution of proteins and their domains. MDAT is coded in C++, and the source code is freely available for download at http://www.bornberglab.org/pages/mdat.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-014-0442-7) contains supplementary material, which is available to authorized users.     

Investigation on Mitochondrial tRNA<Superscript>Leu/Lys</Superscript>, NDI and ATPase 6/8 in Iranian Multiple Sclerosis Patients

As with chromosomal DNA, the mitochondrial DNA (mtDNA) can contain mutations that are highly pathogenic .In fact, many diseases of the central nervous system are known to be caused by mutations in mtDNA. Dysfunction of the mitochondrial Respiratory Chain (RC) has been shown in patients with neurological disease including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Multiple sclerosis (MS). MS is a demyelinating disease of central nervous system characterized by morphological hallmarks of inflammation, demyelination and axonal loss. Considering this importance, we decided to investigate several highly mutative parts of mtDNA for point mutations as MT-LTI (tRNA^{Leucine1(UUA/G)}), MT-NDI (NADH Dehydrogenase subunit 1), MT-COII (Cytochrome c oxidase subunit II), MT-TK (tRNA^Lysine), MT-ATP8 (ATP synthase subunit F0 8) and MT-ATP6 (ATP synthase subunit F0 6) in 20 Iranian MS patients and 80 age-matched control subjects by PCR and automated DNA sequencing to evaluate any probable point mutations. Our results revealed that 15 (75%) out of 20 MS patients had point mutations. Some of point mutations were newly found in this study. This study suggested that point mutation occurred in mtDNA might be involved in pathogenesis of MS.     

Note on Confidence Regions in Multiple Assays

This note is in continuation of the author's results on ’classical‘ confidence regions for relative potencies in multiple assays (Bennett, 1987). It is shown by the use of a Bonferroni inequality (e.g. Miller, ch. 2, 1980) that approximate confidence regions for the relative potencies {M_i} i = 1, …, p may also be obtained directly. A comparison with the classical regions is made for the case: p = 2 using Finney's example (1978, ch. 2).     

Hierarchical testing of variable importance

A frequently encountered challenge in high-dimensional regressionis the detection of relevant variables. Variable selection suffersfrom instability and the power to detect relevant variablesis typically low if predictor variables are highly correlated.When taking the multiplicity of the testing problem into account,the power diminishes even further. To gain power and insight,it can be advantageous to look for influence not at the levelof individual variables but rather at the level of clustersof highly correlated variables. We propose a hierarchical approach.Variable importance is first tested at the coarsest level, correspondingto the global null hypothesis. The method then tries to attributeany effect to smaller subclusters or even individual variables.The smallest possible clusters, which still exhibit a significantinfluence on the response variable, are retained. It is shownthat the proposed testing procedure controls the familywiseerror rate at a prespecified level, simultaneously over allresolution levels. The method has power comparable to the Bonferroni–Holmprocedure on the level of individual variables and dramaticallylarger power for coarser resolution levels. The best resolutionlevel is selected adaptively.     

The generalized multiplicative model for viability selection at multiple loci

Selection due to differential viability is studied in an n-locus two-allele model using a set indexation that allows the simplicity of the one-locus two-allele model to be carried to multi-locus models. The existence condition is analyzed for polymorphic equilibria with linkage equilibrium: Robbins' equilibria. The local stability condition is given for the Robbins' equilibria on the boundaries in the generalized non-epistatic selection regimes of Karlin and Liberman (1979). These generalized non-epistatic regimes include the additive selection model, the multiplicative selection model and the multiplicative interaction model, and their symmetric versions cover all the symmetric viability models.Research supported by grant no. 11-7805 from the Danish Natural Science Research Council, by NIH grant GM 28016, by a fellowship from the Research Foundation of Aarhus University, and by a visiting fellowship from the University of New England, N.S.W.     

Monitoring clinical trials with multiple arms

In order to benefit from the substantial overhead expenses of a large group sequential clinical trial, the simultaneous investigation of several competing treatments becomes more popular. If at some interim analysis any treatment arm reveals itself to be inferior to any other treatment under investigation, this inferior arm may be or may even need to be dropped for ethical and/or economic reasons. Recently proposed methods for monitoring and analysis of group sequential clinical trials with multiple treatment arms are compared and discussed. The main focus of the article is on the application and extension of (adaptive) closed testing procedures in the group sequential setting that strongly control the familywise error rate. A numerical example is given for illustration.     

Multiple forms of carboxylesterase activity in Acinetobacter calcoaceticus

A carboxylesterase activity (E.C.3.1.1) was found in all four strains of Acinetobacter calcoaceticus tested. The activity was present in both 2 X 10(4) gav h-1 supernatant and bacterial wall-membrane fractions. The activity in the supernatant was in two molecular weight forms, the predominant form with a Mr of about 10(3) K and a minor form Mr approximately 600 K. The activity was inhibited by phenylmethylsulfonyl fluoride. SDS-PAGE showed that in A. calcoaceticus NCIB 8250 the activity was composed of three components of Mr 43, 40 and 38 K. The individual components showed different activities with 1- or 2-naphthyl esters. Of the other strains used, one showed a nearly identical pattern of component activities, while the other two showed only two component activities.     

Analysis of extended HLA haplotypes in multiple sclerosis and narcolepsy families confirms a predisposing effect for the class I region in Tasmanian MS patients

Human leucocyte antigen (HLA)-DRB1*15 is associated with predisposition to multiple sclerosis (MS), although conjecture surrounds the possible involvement of an alternate risk locus in the class I region of the HLA complex. We have shown previously that an alternate MS risk allele(s) may be encompassed by the telomerically extended DRB1*15 haplotype, and here, we have attempted to map the putative variant. Thirteen microsatellite markers encompassing a 6.79-megabase (D6S2236-G51152) region, and the DRB1 and DQB1 genes, were genotyped in 166 MS simplex families and 104 control families from the Australian State of Tasmania and 153 narcolepsy simplex families (trios) from the USA. Complementary approaches were used to investigate residual predisposing effects of microsatellite alleles comprising the extended DRB1*15 haplotype taking into account the strong predisposing effect of DRB1*15: (1) Disease association of the extended DRB1*15 haplotype was compared for MS and narcolepsy families--predisposing effects were observed for extended class I microsatellite marker alleles in MS families, but not narcolepsy families; (2) disease association of the extended DRB1*15 haplotype was investigated after conditioning MS and control haplotypes on the absence of DRB1*15--a significant predisposing effect was observed for a 627-kb haplotype (D6S258 allele 8-MOGCA allele 4; MOG, myelin oligodendrocyte glycoprotein) spanning the extended class I region. MOGCA allele 4 displayed the strongest predisposing effect in DRB1*15-conditioned haplotypes (p = 0.0006; OR 2.83 [1.54-5.19]). Together, these data confirm that an alternate MS risk locus exists in the extended class I region in Tasmanian MS patients independent of DRB1*15.     

多发性硬化生物标记物的研究进展

多发性硬化(MS)是主要以中枢神经系统(CNS)白质脱髓鞘病变为主要特点的自身免疫性疾病。生物标记物是中枢神经系统自身免疫性疾病病因、诊断和预后的重要参考因素,因为他们可能反映遗传以及环境变化所引起的某些免疫反应的存在,性质和强度。因此生物标记有助于MS的早期诊断和鉴别诊断,指导治疗方案,推断MS疾病活动性,以及判断疗效。本文概述了多发性硬化领域当前的生物标记物研究状况及其相关的临床实践,并通过对三种具有较大潜力的生物标记物与病理的特异性、灵敏度、可靠性和临床实用工具进行分析,以确定最优化的治疗以防止致残,同时还可以对疾病修饰药物的有效性进行测试。