Testing for association in the presence of population stratification: a simulation study comparing the S-TDT, STRAT and the GC

A novel approach for association testing in the presence of population stratification has been introduced by Pritchard et al. (2000a) and Pritchard et al. (2000b). The structured association approach is a two-tiered procedure that first estimates the population structure and then tests the null hypothesis H0: 'no association within subpopulations' in the second step. A power comparison of the stratified test for association (STRAT) (Pritchard et al., 2000b) and the Transmission-Disequilibrium-Test (TDT) (Spielman and Ewens, 1993a) in a simulation framework showed superiority of STRAT if allele frequencies or associations between allele and disease differ strongly in subpopulations. In more homogeneous situations, the TDT had greater power than STRAT. However, the TDT, based on family trios,that uses population controls, needs 50% more genotyping compared to STRAT. The Sib-Transmission-Disequilibrium-Test (S-TDT) needs the same amount of genotyping since it relays in its minimal configuration on pairs of siblings. This raises the question how the S-TDT (Spielman and Ewens, 1998a) performs compared to the population based methods STRAT and Genomic Controls (GC). In this paper, we present a simulation study accounting for two different models of population stratification in different settings of allele frequencies and under different risk models. The results showed that under a discrete as well as under an admixed population model, STRAT strongly outperformed the S-TDT and the GC when different alleles were associated in different subpopulations. In contrast, the S-TDT had greater power than STRAT when the same allele was associated in both subpopulations. Here, the GC was sometimes even more powerful than the S-TDT, depending on the population model and the allele frequency differences. A general recommendation for the use of one of the tests can therefore not be given.     

心衰生物标记物研究新进展

心力衰竭(心衰)是临床最常见的危重疾病之一,其致死率不低于某些癌症。随着现代医学进展,年龄依赖性死亡率明显下降,冠脉事件显著减少,患者生存时间延长,心衰患病率较前增加。针对心衰的研究不断更新,心衰的病理生理机制日益趋向完善,不仅仅涉及先前众所周知的心肌损伤或者心脏前后负荷增加,更多因素先后被发现参与心衰的发生、发展,包括神经内分泌机制、炎症反应,内分泌信号系统和生化因素等。伴随心衰病理生理过程产生了一系列的生物标记物,某些生物标记物在协助临床医生诊疗心衰患者方面发挥重要作用。具体包括神经激素类生物(例如:脑钠肽、氨基末端-pro BNP、心房钠尿肽前体中段、肾上腺髓质素前体中段和嗜铬素A),炎症因子类生物标记物(例如:CRP、IL-6和ST2),内分泌生物标志物(例如:脂联素、抵抗素、瘦素和醛固酮),其他生物标记物(包括:肌钙蛋白I/T、乳糖凝集素-3、胱氨酸蛋白酶抑制剂C、生长分化因子-15和基质金属蛋白酶)。生物标记物凭借其高度敏感性及特异性,在心衰的诊断、危险分层及评估预后等方面发挥重要作用。本文就心衰生物标记物最新研究进展做一综述。     

A simple and improved correction for population stratification in case-control studies

Population stratification remains an important issue in case-control studies of disease-marker association, even within populations considered to be genetically homogeneous. Campbell et al. (Nature Genetics 2005;37:868-872) illustrated this by showing that stratification induced a spurious association between the lactase gene (LCT) and tall/short status in a European American sample. Furthermore, existing approaches for controlling stratification by use of substructure-informative loci (e.g., genomic control, structured association, and principal components) could not resolve this confounding. To address this problem, we propose a simple two-step procedure. In the first step, we model the odds of disease, given data on substructure-informative loci (excluding the test locus). For each participant, we use this model to calculate a stratification score, which is that participant's estimated odds of disease calculated using his or her substructure-informative-loci data in the disease-odds model. In the second step, we assign subjects to strata defined by stratification score and then test for association between the disease and the test locus within these strata. The resulting association test is valid even in the presence of population stratification. Our approach is computationally simple and less model dependent than are existing approaches for controlling stratification. To illustrate these properties, we apply our approach to the data from Campbell et al. and find no association between the LCT locus and tall/short status. Using simulated data, we show that our approach yields a more appropriate correction for stratification than does principal components or genomic control.     

Effect of population stratification on case-control association studies. II. False-positive rates and their limiting behavior as number of subpopulations increases

There has been considerable debate in the literature concerning bias in case-control association mapping studies due to population stratification. In this paper, we perform a theoretical analysis of the effects of population stratification by measuring the inflation in the test's type I error (or false-positive rate). Using a model of stratified sampling, we derive an exact expression for the type I error as a function of population parameters and sample size. We give necessary and sufficient conditions for the bias to vanish when there is no statistical association between disease and marker genotype in each of the subpopulations making up the total population. We also investigate the variation of bias with increasing subpopulations and show, both theoretically and by using simulations, that the bias can sometimes be quite substantial even with a very large number of subpopulations. In a companion simulation-based paper (Heiman et al., Part I, this issue), we have focused on the CRR (confounding risk ratio) and its relationship to the type I error in the case of two subpopulations, and have also quantified the magnitude of the type I error that can occur with relatively low CRR values.     

Do southern elephant seals show density dependence in fecundity?

Here we provide an alternative interpretation to that of Pistorius et al. (2001), concerning density-dependent increases in fecundity resulting in population regulation of the southern elephant seal population at Marion Island. We do not contradict the findings of Pistorius et al. (2001), because it does appear: (1) that a change in fecundity has been observed, and (2) that some factor related to food supply is the most likely cause for an observed population decline and increase in reproductive performance. The main observation leading to the interpretation of density-dependent feedback in the population of southern elephant seals at Marion Island (one of the Prince Edward Islands) is that there has been a reduction in the population's rate of decline in recent years (reported by Pistorius et al. (1999b)), and that this could have resulted from a per capita increase in food availability. However, because rates of population change are rarely linearly constant, changes in population size should be expressed on a logarithmic, rather than a linear scale, as used by Pistorius et al. (1999b). Re-plotting the linear values of Pistorius et al. (1999b) on the natural logarithmic scale gave no clear change in the rate of population decline; therefore, we conclude that the rate of population change (decline) has remained constant from 1986 to 1997 (r=-0.0439). The Marion Island population is part of the larger Kerguelen population, and there might be considerable overlap in the foraging areas, and possibly prey, exploited by elephant seals from all sub-populations within this larger population. Changes in the number of intra-specific resource competitors at Marion Island are therefore unlikely to alter per capita food availability since the Marion population constitutes approximately 1% of the total Kerguelen population. We propose an alternative hypothesis that the present data support a mechanism driving the proposed increase in per capita food supply through changes in either: (1) inter-specific food competition, (2) rates of predation, (3) changes in weather pattern or (4) disease.     

Robust Rare-Variant Association Tests for Quantitative Traits in General Pedigrees

Next-generation sequencing technology has propelled the development of statistical methods to identify rare polygenetic variation associated with complex traits. The majority of these statistical methods are designed for case–control or population-based studies, with few methods that are applicable to family-based studies. Moreover, existing methods for family-based studies mainly focus on trios or nuclear families; there are far fewer existing methods available for analyzing larger pedigrees of arbitrary size and structure. To fill this gap, we propose a method for rare-variant analysis in large pedigree studies that can utilize information from all available relatives. Our approach is based on a kernel machine regression (KMR) framework, which has the advantages of high power, as well as fast and easy calculation of p-values using the asymptotic distribution. Our method is also robust to population stratification due to integration of a QTDT framework (Abecasis et al., Eur J Hum Genet 8(7):545–551, 2000b) with the KMR framework. In our method, we first calculate the expected genotype (between-family component) of a non-founder using all founders’ information and then calculate the deviates (within-family component) of observed genotype from the expectation, where the deviates are robust to population stratification by design. The test statistic, which is constructed using within-family component, is thus robust to population stratification. We illustrate and evaluate our method using simulated data and sequence data from Genetic Analysis Workshop 18.     

Joint analysis for genome-wide association studies in family-based designs

In family-based data, association information can be partitioned into the between-family information and the within-family information. Based on this observation, Steen et al. (Nature Genetics. 2005, 683-691) proposed an interesting two-stage test for genome-wide association (GWA) studies under family-based designs which performs genomic screening and replication using the same data set. In the first stage, a screening test based on the between-family information is used to select markers. In the second stage, an association test based on the within-family information is used to test association at the selected markers. However, we learn from the results of case-control studies (Skol et al. Nature Genetics. 2006, 209-213) that this two-stage approach may be not optimal. In this article, we propose a novel two-stage joint analysis for GWA studies under family-based designs. For this joint analysis, we first propose a new screening test that is based on the between-family information and is robust to population stratification. This new screening test is used in the first stage to select markers. Then, a joint test that combines the between-family information and within-family information is used in the second stage to test association at the selected markers. By extensive simulation studies, we demonstrate that the joint analysis always results in increased power to detect genetic association and is robust to population stratification.     

Model for the chemotactic response of a bacterial population.

We present a mathematical model for the motion of a bacterial population in prescribed attractant or repellent gradients. The model is suggested by the observations of Mesibov et al. (1973, J. Gen. Physiol. 62:203) and Brown and Berg (1974, Proc. Natl. Acad. Sci. U.S.A. 71:1388) who found that the sensitivity of the chemotactic response depends on the concentration of attractant. Predictions of the theory are in general agreement with the experiments of Dahlquist et al. (1972, Nat. New Biol. 236:120) and of Mesibov et al. on populations of motile bacteria in fixed attractant gradients. Additional tests of the model are proposed.     

A note on efficient computation of haplotypes via perfect phylogeny.

The problem of inferring haplotype phase from a population of genotypes has received a lot of attention recently. This is partly due to the observation that there are many regions on human genomic DNA where genetic recombination is rare (Helmuth, 2001; Daly et al., 2001; Stephens et al., 2001; Friss et al., 2001). A Haplotype Map project has been announced by NIH to identify and characterize populations in terms of these haplotypes. Recently, Gusfield introduced the perfect phylogeny haplotyping problem, as an algorithmic implication of the no-recombination in long blocks observation, together with the standard population-genetic assumption of infinite sites. Gusfield's solution based on matroid theory was followed by direct theta(nm2) solutions that use simpler techniques (Bafna et al., 2003; Eskin et al., 2003), and also bound the number of solutions to the PPH problem. In this short note, we address two questions that were left open. First, can the algorithms of Bafna et al. (2003) and Eskin et al. (2003) be sped-up to O(nm + m2) time, which would imply an O(nm) time-bound for the PPH problem? Second, if there are multiple solutions, can we find one that is most parsimonious in terms of the number of distinct haplotypes. We give reductions that suggests that the answer to both questions is "no." For the first problem, we show that computing the output of the first step (in either method) is equivalent to Boolean matrix multiplication. Therefore, the best bound we can presently achieve is O(nm(omega-1)), where omega < or = 2.52 is the exponent of matrix multiplication. Thus, any linear time solution to the PPH problem likely requires a different approach. For the second problem of computing a PPH solution that minimizes the number of distinct haplotypes, we show that the problem is NP-hard using a reduction from Vertex Cover (Garey and Johnson, 1979).     

PFDB: a generic protein family database integrating the CATH domain structure database with sequence based protein family resources

MOTIVATION: The PFDB (Protein Family Database) is a new database designed to integrate protein family-related data with relevant functional and genomic data. It currently manages biological data for three projects-the CATH protein domain database (Orengo et al., 1997; Pearl et al., 2001), the VIDA virus domains database (Albà et al., 2001) and the Gene3D database (Buchan et al., 2001). The PFDB has been designed to accommodate protein families identified by a variety of sequence based or structure based protocols and provides a generic resource for biological research by enabling mapping between different protein families and diverse biochemical and genetic data, including complete genomes. RESULTS: A characteristic feature of the PFDB is that it has a number of meta-level entities (for example aggregation, collection and inclusion) represented as base tables in the final design. The explicit representation of relationships at the meta-level has a number of advantages, including flexibility-both in terms of the range of queries that can be formulated and the ability to integrate new biological entities within the existing design. A potential drawback with this approach-poor performance caused by the number of joins across meta-level tables-is avoided by implementing the PFDB with materialized views using the mature relational database technology of Oracle 8i. The resultant database is both fast and flexible. This paper presents the principles on which the database has been designed and implemented, and describes the current status of the database and query facilities supported.     

A theory of follicle selection: II. Computer simulation of estradiol administration in the primate

A theory of follicle selection (Lacker, 1981) is tested in the primate by simulating the effects of estradiol administration at different times, strengths, and durations during the follicular phase of the menstrual cycle (Clark et al., 1981; Zeleznik, 1981; Dierschke et al., 1985). The theory can account for the observed atretogenic effects of circulating estradiol on follicle development including full, partial, and delayed atresia of the dominant follicle (Dierschke et al., 1985) and can explain why similar estradiol doses achieve different qualitative effects when given at different times during the cycle. The theory predicts that recovery from early atresia may be possible, and it can also account for the loss of control in the number of maturing follicles that has been observed when estradiol antibodies are given in the midfollicular phase (Zeleznik et al., 1985). These results support the hypothesis that the selection mechanism in the primate is a consequence of feedback involving an essentially equipotent follicle population interacting through circulating estradiol and pituitary gonadotropins. A quantitative test of the theory awaits experimental identification of the maturation surfaces that are predicted by it. An experimental design for this purpose is proposed.     

AN ANALYSIS OF PROCEDURES FOR IMPLEMENTING THE DYNAMIC RESPONSE METHOD

Abstract: A new method, the "dynamic response method," was developed (DeMaster et al. 1982) in an attempt to use time series data on relative population sizes to satisfy the requirements of the Marine Mammal Protection Act of 1972 for maintaining an "optimum sustainable population" of marine mammals. Three methods of implementing this approach were studied, using a computer simulation of stochastic population growth with density-dependence operating on first-year survival in the form of a generalized-logistic function. Methods developed by Gerrodette (1988) and Boveng et al. (1988) appeared to be less sensitive than desirable when used with the simulated population data. The third method, developed in this study, offers better protection against "Type II error" (failing to identify populations in the optimum sustainable population range), particularly when combined with Gerrodette's (1988) approach.     

Population-genetic basis of haplotype blocks in the 5q31 region

We investigated patterns of nucleotide variation in the 5q31 region identified by Daly et al. as containing haplotype blocks, to determine whether the blocklike pattern requires the assumption of hotspots in recombination. Using extensive simulations that generate data matched to the Daly et al. data set in (a) the method of ascertainment of single-nucleotide polymorphisms, (b) the heterozygosity of ascertained markers, (c) the number of block boundaries, and (d) the diversity of haplotypes within blocks, we show that the patterns found in the Daly et al. data are not consistent with the assumption of uniform recombination in a population of constant size but are consistent either with the presence of hotspots in a population of constant size or with the absence of hotspots if there was a period of rapid population growth. We further show that estimates of local recombination rate can distinguish between population growth and hotspots as the primary cause of a blocklike pattern. Estimates of local recombination rates for the Daly et al. data do not indicate the presence of recombination hotspots.     

Epstein-Barr virus DNA XII. A variable region of the Epstein-Barr virus genome is included in the P3HR-1 deletion.

The P3HR-1 subclone of Jijoye differs from Jijoye and from other Epstein-Barr virus (EBV)-infected cell lines in that the virus produced by P3HR-1 cultures lacks the ability to growth-transform normal B lymphocytes (Heston et al., Nature (London) 295:160-163, 1982; Miller et al., J. Virol. 18:1071-1080, 1976; Miller et al., Proc. Natl. Acad. Sci. U.S.A. 71:4006-4010, 1974; Ragona et al., Virology 101:553-557, 1980). The P3HR-1 virus was known to be deleted for a region which encodes RNA in latently infected, growth-transformed cells (Bornkamm et al., J. Virol. 35:603-618, 1980; Heller et al., J. Virol. 38:632-648, 1981; King et al., J. Virol. 36:506-518, 1980; Raab-Traub et al., J. Virol. 27:388-398, 1978; van Santen et al., Proc. Natl. Acad. Sci. U.S.A. 78:1930-1934, 1980). This deletion is now more precisely defined. The P3HR-1 genome contains less than 170 base pairs (and possibly none) of the 3,300-base pair U2 region of EBV DNA and is also lacking IR2 (a 123-base pair repeat which is the right boundary of U2). A surprising finding is that EBV isolates vary in part of the U2 region. Two transforming EB viruses, AG876 and Jijoye, are deleted for part of the U2 region including most or all of a fragment, HinfI-c, which encodes part of one of the three more abundant cytoplasmic polyadenylated RNAs of growth-transformed cells (King et al., J. Virol. 36:506-518, 1980; King et al., J. Virol. 38:649-660, 1981; van Santen et al., Proc. Natl. Acad. Sci. U.S.A. 78:1930-1934).     

Reply to response to Dyck et al. (2007) on polar bears and climate change in western Hudson Bay by Stirling et al. (2008)

We address the three main issues raised by Stirling et al. [Stirling, I., Derocher, A.E., Gough, W.A., Rode, K., in press. Response to Dyck et al. (2007) on polar bears and climate change in western Hudson Bay. Ecol. Complexity]: (1) evidence of the role of climate warming in affecting the western Hudson Bay polar bear population, (2) responses to suggested importance of human–polar bear interactions, and (3) limitations on polar bear adaptation to projected climate change. We assert that our original paper did not provide any “alternative explanations [that] are largely unsupported by the data” or misrepresent the original claims by Stirling et al. [Stirling, I., Lunn, N.J., Iacozza, I., 1999. Long-term trends in the population ecology of polar bears in western Hudson Bay in relation to climate change. Arctic 52, 294–306], Derocher et al. [Derocher, A.E., Lunn, N.J., Stirling, I., 2004. Polar bears in a warming climate. Integr. Comp. Biol. 44, 163–176], and other peer-approved papers authored by Stirling and colleagues. In sharp contrast, we show that the conclusion of Stirling et al. [Stirling, I., Derocher, A.E., Gough, W.A., Rode, K., in press. Response to Dyck et al. (2007) on polar bears and climate change in western Hudson Bay. Ecol. Complexity] – suggesting warming temperatures (and other related climatic changes) are the predominant determinant of polar bear population status, not only in western Hudson (WH) Bay but also for populations elsewhere in the Arctic – is unsupportable by the current scientific evidence.The commentary by Stirling et al. [Stirling, I., Derocher, A.E., Gough, W.A., Rode, K., in press. Response to Dyck et al. (2007) on polar bears and climate change in western Hudson Bay. Ecol. Complexity] is an example of uni-dimensional, or reductionist thinking, which is not useful when assessing effects of climate change on complex ecosystems. Polar bears of WH are exposed to a multitude of environmental perturbations including human interference and factors (e.g., unknown seal population size, possible competition with polar bears from other populations) such that isolation of any single variable as the certain root cause (i.e., climate change in the form of warming spring air temperatures), without recognizing confounding interactions, is imprudent, unjustified and of questionable scientific utility. Dyck et al. [Dyck, M.G., Soon, W., Baydack, R.K., Legates, D.R., Baliunas, S., Ball, T.F., Hancock, L.O., 2007. Polar bears of western Hudson Bay and climate change: Are warming spring air temperatures the “ultimate” survival control factor? Ecol. Complexity, 4, 73–84. doi:10.1016/j.ecocom.2007.03.002] agree that some polar bear populations may be negatively impacted by future environmental changes; but an oversimplification of the complex ecosystem interactions (of which humans are a part) may not be beneficial in studying external effects on polar bears. Science evolves through questioning and proposing hypotheses that can be critically tested, in the absence of which, as Krebs and Borteaux [Krebs, C.J., Berteaux, D., 2006. Problems and pitfalls in relating climate variability to population dynamics. Clim. Res. 32, 143–149] observe, “we will be little more than storytellers.”     

Target reproduction numbers for reaction-diffusion population models

A very important population threshold quantity is the target reproduction number, which is a measure of control effort required for a target prevention, intervention or control. This concept, as a generalization of type reproduction number, was first introduced in Shuai et al. (J Math Biol 67:1067–1082, 2013) for nonnegative matrices with immediate applications to compartmental population models of ordinary differential equations. The current paper is devoted to the study of all target reproduction numbers for reaction-diffusion population models with compartmental structure. It turns out that the target reproduction number can be regarded as the basic reproduction number of a modified system, where the state of newborn individuals is limited to the target control set and the offspring from the non-target set is regarded as a part of the transition. In other words, the target reproduction number can be interpreted as the expected number of offspring in a specific target set that a primary newborn individual of the same set would produce during its lifetime. We also characterize the target reproduction number so that it can be easily computed numerically for reaction-diffusion models. At the end, we demonstrate our theoretical observations using two examples.

     

八种海洋盾纤类纤毛虫的形态学研究

对采自山东、广东和香港沿海的八种盾纤类纤毛虫: 冠帆口虫、维亚可夫帆口虫、蠕形康纤虫、贪食迈阿密虫、异海洋尾丝虫、中华后阿脑虫和两种蟹栖异阿脑虫相似种进行了形态学研究。其中, 中国南海新记录种维亚可夫帆口虫种群与Wang, et al.所描述种群以及中华后阿脑虫新种群与Song Wilbert记述的青岛种群和南极种群相比, 在个体大小和体动基列数目上均有所差异; 贪食迈阿密虫潍坊种群的体动基列恒为12列, 与Song Wilbert的报道有较大差异。两种异阿脑虫与蟹栖异阿脑虫在口纤毛器结构和体形上完全相似, 但在体动基列数目上有明显差异, 因数据不足, 暂定为蟹栖异阿脑虫相似种。