Asthma definitions, relative validity and impact on known risk factors in young Brazilians

BACKGROUND: An asthma score was proposed in the European Community Respiratory Health Survey (ECRHS) framework, as dichotomous definitions could be less appropriate in the study of chronic diseases. The aims of this study were to assess the value of this asthma score in comparison with other definitions of asthma in another population setting, using as criteria bronchial hyperresponsiveness (BHR) to methacholine and diagnosed asthma, and the association of these definitions to known risk factors of asthma. METHODS: We used the ECRHS questionnaire on 2063 Brazilians, aged 23-25 years, and measured their BHR. We assessed the positive and negative likelihood ratios (PLR and NLR) of the asthma score (0-8), a three question score (ECRHS definition) and single asthma symptoms in relation to BHR and diagnosed asthma. RESULTS: The PLR were relatively low for all asthma definitions with odd ratios varying from 1.47 for asthma score to 5.50 for wheeze and waking with breathlessness without a cold. The NLR were near 1. The PLR were lower for assessments using the score than for dichotomous assessments or the ECRHS definition. The PLR increased with asthma scores, but the prevalence with higher scores was too low for useful analysis. The asthma score was slightly better for identifying associations from a set of known risk factors than the other two approaches. CONCLUSION: Our study provided little support for a greater validity of this asthma score over other asthma definitions, and only marginal advantage for identifying risk factors.     

Likelihood Ratio Tests in Rare Variant Detection for Continuous Phenotypes

It is believed that rare variants play an important role in human phenotypes; however, the detection of rare variants is extremely challenging due to their very low minor allele frequency. In this paper, the likelihood ratio test (LRT) and restricted likelihood ratio test (ReLRT) are proposed to test the association of rare variants based on the linear mixed effects model, where a group of rare variants are treated as random effects. Like the sequence kernel association test (SKAT), a state‐of‐the‐art method for rare variant detection, LRT and ReLRT can effectively overcome the problem of directionality of effect inherent in the burden test in practice. By taking full advantage of the spectral decomposition, exact finite sample null distributions for LRT and ReLRT are obtained by simulation. We perform extensive numerical studies to evaluate the performance of LRT and ReLRT, and compare to the burden test, SKAT and SKAT‐O. The simulations have shown that LRT and ReLRT can correctly control the type I error, and the controls are robust to the weights chosen and the number of rare variants under study. LRT and ReLRT behave similarly to the burden test when all the causal rare variants share the same direction of effect, and outperform SKAT across various situations. When both positive and negative effects exist, LRT and ReLRT suffer from few power reductions compared to the other two competing methods; under this case, an additional finding from our simulations is that SKAT‐O is no longer the optimal test, and its power is even lower than that of SKAT. The exome sequencing SNP data from Genetic Analysis Workshop 17 were employed to illustrate the proposed methods, and interesting results are described.     

A Note on Allelic Tests in Case-Control Association Studies

This paper reconsiders the relevant contribution of Sasieni in the validity of allele‐based tests in case‐control genetic association studies. In particular, the author clearly demonstrates that the classical chi‐square test applied to allelic contingency tables is biased when the combined case‐control population is not in Hardy‐Weinberg equilibrium. As an alternative, he suggests using the Cochran‐Armitage test for trends by basing his argument on the fact that these two tests are asymptotically equivalent at the Hardy‐Weinberg equilibrium. However he only demonstrates the equality of the statistics when the observed genotypic proportions are strictly in equilibrium ‐ which does not formally imply the suggested, and often accepted, asymptotic behavior. In this short communication, we complement this contribution by providing the proof that allelic and trend statistics are asymptotically equivalent under the conditions mentioned above. In addition, since the ‘biased’ allelic test is still widely used in the literature, we briefly discuss the different alternatives that have been subsequently developed, based on Sasieni's conclusions.     

Tests for Candidate-Gene Association Using Case-Parents Design

In the case‐parents design for testing candidate‐gene association, the conditional likelihood method based on genotype relative risks has been developed recently. A specific relation of the genotype relative risks is referred to as a genetic model. The efficient score tests have been used when the genetic model is correctly specified under the alternative hypothesis. In practice, however, it is usually not able to specify the genetic model correctly. In the latter situation, tests such as the likelihood ratio test (LRT) and the MAX3 (the maximum of the three score statistics for dominant, additive, and recessive models) have been used. In this paper, we consider the restricted likelihood ratio test (RLRT). For a specific genetic model, simulation results demonstrate that RLRT is asymptotically equivalent to the score test, and both are more powerful than the LRT. When the genetic model cannot be correctly specified, the simulation results show that RLRT is most robust and powerful in the situations we studied. MAX3 is the next most robust and powerful test. The TDT is the easiest statistic to compute, compared to MAX3 and RLRT. When the recessive model can be eliminated, it is also as robust and powerful as RLRT for other genetic models.     

A Unified Approach to Modelling Linkage to Quantitative and Qualitative Traits

For quantitative traits with a genetic component, random effects approaches are used to test for linkage at observed marker loci. We propose to use these approaches also for binary outcomes observed in sib pairs derived from a population‐based cohort study. In addition to a random effect modelling correlation due to polygenic effect, a random effect is included to model the correlation between siblings due to sharing alleles identical by descent (IBD) at the observed marker locus. A two‐step analysis is proposed. Firstly, score statistics are computed to test whether correlation is present in the data. Secondly, random effects models are fitted, yielding heritability estimates. To illustrate the methods, data on the contribution of the COL2A1 gene to various binary and quantitative outcomes including the presence of Heberden's nodes and bone mineral density (BMD) are analysed. For most of the traits studied, the score statistics were significant, indicating the presence of genetic effects. For BMD and for Heberden's nodes, the variance explained by the marker locus was 44% (P = 0.0008) and 15% (P = 0.38) respectively. We conclude that the score statistics can be used as a preliminary data analysis. In more sophisticated analysis, heritabilities can be estimated by fitting random effects models.     

Robust Quantitative Trait Association Tests in the Parent-Offspring Triad Design: Conditional Likelihood-Based Approaches

Association studies, based on either population data or familial data, have been widely applied to mapping of genes underlying complex diseases. In family-based association studies, using case-parent triad families, the popularly used transmission/disequilibrium test (TDT) was proposed for avoidance of spurious association results caused by other confounders such as population stratification. Originally, the TDT was developed for analysis of binary disease data. Extending it to allow for quantitative trait analysis of complex diseases and for robust analysis of binary diseases against the uncertainty of mode of inheritance has been thoroughly discussed. Nevertheless, studies on robust analysis of quantitative traits for complex diseases received relatively less attention. In this paper, we use parent-offspring triad families to demonstrate the feasibility of establishment of the robust candidate-gene association tests for quantitative traits. We first introduce the score statistics from the conditional likelihoods based on parent-offspring triad data under various genetic models. By applying two existing robust procedures we then construct the robust association tests for analysis of quantitative traits. Simulations are conducted to evaluate empirical type I error rates and powers of the proposed robust tests. The results show that these robust association tests do exhibit robustness against the effect of misspecification of the underlying genetic model on testing powers.     

采用广义似然比检测的肌肉收缩起始时刻判断算法

肌电假肢利用残肢残存肌肉的肌电信号实行对假肢的控制。对于低信噪比的残肢表面肌电,本研究采用广义似然比检测方法判断肌肉收缩起始时刻,其中判别阈值与肌电信号信噪比有关。针对不同信噪比的模拟肌电信号,采用离线仿真方法得到肌肉收缩起始时刻检测误差最小的判别阈值,得到信噪比-经验阈值拟合曲线,确定信噪比与阈值的对应关系;根据肌电信噪比由阈值拟合曲线得到判别阈值,采用似然比检测算法在线分析肌肉收缩的起始时刻。与传统算法比较,对于模拟肌电信号,本算法误差均值和标准差分别减小35%和43%;对于真实肌电信号,误差均值和标准差分别减少29%和23%。可见在小信噪比条件下广义似然比检测算法判断肌肉收缩起始时刻较传统算法更为准确。     

A Comparison of the Likelihood Ratio Test and the Variance‐Stabilising Transformation‐Based Tests for Detecting Association of Rare Variants

In a recent paper in this journal, the use of variance‐stabilising transformation techniques was proposed to overcome the problem of inadequacy in normality approximation when testing association for a low‐frequency variant in a case‐control study. It was shown that tests based on the variance‐stabilising transformations are more powerful than Fisher's exact test while controlling for type I error rate. Earlier in the journal, another study had shown that the likelihood ratio test (LRT) is superior to Fisher's exact test, Wald's test, and Pearson's χ² test in testing association for low‐frequency variants. Thus, it is of interest to make a direct comparison between the LRT and the tests based on the variance‐stabilising transformations. In this commentary, we show that the LRT and the variance‐stabilising transformation‐based tests have comparable power greater than Fisher's exact test, Wald's test, and Pearson's χ² test.     

考虑突变影响的亲子鉴定研究

目的基于对突变问题的考虑和实验数据,提出达到科学鉴定结论的基本要求,供制定亲子鉴定标准参考。方法检测15个短串联重复序列基因座,包括CSF1 PO、FGA、TH01、TPOX、VWA、D3S1358、D5S818、D7S820、D8S1179、D13S317、D16S539、D18S51、D21S11等13个CODIS基因座以及PentaD和PentaE基因座,统计肯定父权的母亲、孩子、被告男子3人组合和排除父权的母亲、孩子、被告男子3人组合各100例。结果观察到排除父权的母亲、孩子、被告男子3人组合不符合遗传规律的短串联重复序列基因座数。获得了父权指数值的各种分布,包括模拟突变情况下每例父权指数的变化。结论为了避免潜在突变影响,任何情况下都不能仅根据一个遗传标记排除父权。累积非父排除概率和累计父权指数的阈值对于肯定父权和排除父权极为重要。系统的累积非父排除概率和累计父权指数达到一定阈值后,可以获得科学的鉴定结论。在不能达到阈值时,必须通过增加检测的遗传标记数量来达到要求。     

A Note on the Power to Detect Transmission Distortion in Parent-Child Trios via the Transmission Disequilibrium Test

Transmission distortion refers to deviation from the normal 50:50 transmission of alleles from parents to offspring. Identification of genomic regions which undergo distortion is necessary for the correct interpretation of linkage and association studies, since tests of linkage using affected relative pairs and family based tests of association will yield spurious results in the presence of transmission distortion. With the increasing availability of genome-wide high density SNP data (e.g. from the International HapMap project), identification of these loci is now a real possibility. Here we present an analytical formula which demonstrates that the power to detect transmission distortion is a simple function of the number of heterozygous parents in the sample and the level of distortion at the locus. Our results indicate that whilst it will be possible to identify loci undergoing major levels of distortion using tens or hundreds of trios, large sample sizes in the order of tens of thousands of trios will be necessary to detect minor levels of distortion with appreciable power. The corollary is that genome-wide searches are unlikely to identify loci where the level of distortion is small, although they may serve to identify interesting regions worthy of follow up.Edited by Stacey Cherny     

Conservation of the RB1 gene in human and primates

Mutations in the RB1 gene are associated with retinoblastoma, which has served as an important model for understanding hereditary predisposition to cancer. Despite the great scrutiny that RB1 has enjoyed as the prototypical tumor suppressor gene, it has never been the object of a comprehensive survey of sequence variation in diverse human populations and primates. Therefore, we analyzed the coding (2,787 bp) and adjacent intronic and untranslated (7,313 bp) sequences of RB1 in 137 individuals from a wide range of ethnicities, including 19 Asian Indian hereditary retinoblastoma cases, and five primate species. Aside from nine apparently disease-associated mutations, 52 variants were identified. They included six singleton, coding variants that comprised five amino acid replacements and one silent site. Nucleotide diversity of the coding region (pi=0.0763+/-1.35 x 10(-4)) was 52 times lower than that of the noncoding regions (pi=3.93+/-5.26 x 10(-4)), indicative of significant sequence conservation. The occurrence of purifying selection was corroborated by phylogeny-based maximum likelihood analysis of the RB1 sequences of human and five primates, which yielded an estimated ratio of replacement to silent substitutions (omega) of 0.095 across all lineages. RB1 displayed extensive linkage disequilibrium over 174 kb, and only four unique recombination events, two in Africa and one each in Europe and Southwest Asia, were observed. Using a parsimony approach, 15 haplotypes could be inferred. Ten were found in Africa, though only 12.4% of the 274 chromosomes screened were of African origin. In non-Africans, a single haplotype accounted for from 63 to 84% of all chromosomes, most likely the consequence of natural selection and a significant bottleneck in effective population size during the colonization of the non-African continents.     

非文字智力测验的汉族儿童常模

目的：建立一套非文字智力测验的汉族正常儿童年龄常模,用以比较特殊群体的智力。方法：采用分层取样计划。按年龄、性别、地域以及受试者的父母亲的教育和职业等变量来分层。结果：常模样本由取自全国７大行政区中８个省的３～１６岁１５９１名城市儿童所组成,男女接近各半,分成１０个年龄组。分三种常模,即原始分,离差量表分和离差标准分。信度和效度检验结果：６６名儿童相隔１～２周各分测验量表分的重测相关系数为０．４６至０．７８,分测验之间的原始分相关系数为０．４５至０．７８。７４名儿童在本测验的标准分与我国修订的韦氏儿童智力量表的ＶＩＱ,ＰＩＱ和ＦＩＱ的相关系数分别为０．４７,０．６４和０．６０。本常模样本中各分测验各年龄组间成绩差异明显,特别是在１０左右以前。结论：现有结果说明,本测验在汉族儿童中的信、效度比较满意。本测验是测量汉族正常儿童智力的有效手段之一,同时也可作比较正常儿童与特殊群体儿童智力的方法。     

Linkage analysis suggests a locus of ichthyosis vulgaris on 1q22

Ichthyosis vulgaris (IV) is an inherited scaling skin disorder with a prevalence estimated at 2.29% in China. The gene responsible for this disorder has not been elucidated. To find the disease gene, we ascertained two Chinese IV families. Linkage analysis identified an IV locus on chromosome 1q22 with a maximum two-point Lod score of 2.47 at D1S1653 (=0.00). Haplotype analysis placed the critical region in a 7-cM interval defined by D1S1653 and D1S2675. These results provide the basis for further identifying the gene responsible for IV disorder.W. Zhong and B. Cui contributed equally to this work     

Tests of Association Between Quantitative Traits and Haplotypes In A Reduced-Dimensional Space

Candidate gene association tests are currently performed using several intragenic SNPs simultaneously, by testing SNP haplotype or genotype effects in multifactorial diseases or traits. The number of haplotypes drastically increases with an increase in the number of typed SNPs. As a result, large numbers of haplotypes will introduce large degrees of freedom in haplotype‐based tests, and thus limit the power of the tests. In this study we propose using the principal component method to reduce the dimension, and then construct association tests on the lower‐dimensional space to test the association between haplotypes and a quantitative trait using population‐based samples. The proposed method allows ambiguous haplotypes. We use simulation studies to evaluate the type I error rate of the tests, and compare the power of the proposed tests with that of the tests without dimension reduction, and the tests with dimension reduction by merging rare haplotypes. The simulation results show that the proposed tests have correct type I error rates and are more powerful than other tests in most cases considered in our simulation studies.     

The Merits of Testing Hardy-Weinberg Equilibrium in the Analysis of Unmatched Case-Control Data: A Cautionary Note

Testing for departures from the assumption of Hardy-Weinberg equilibrium (HWE) has been widely recommended as a preliminary step in the analysis of genetic case-control studies. Some authors suggest using a two-stage procedure in which gene/disease associations are ultimately evaluated using either the Pearson chi-square procedure or the Cochran-Armitage test for trend. Other authors go further and encourage investigators to discard data that are in violation of HWE, essentially using the test as a tool for identifying genotyping errors. In this paper we show that 1) testing for HWE should not be used as a tool to identify genotyping errors; and 2) it is not necessary, and possibly even harmful, to test the HWE assumption before testing for association between alleles and disease. Instead one should inherently account for deviations from HWE with an adjusted chi-square test statistic, a procedure which in the present context is identical to the trend test. Examples from previous reports are used to illustrate the methodology.     

Linkage analysis of a large swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23

Several reports have indicated genetic linkage between markers on the short arm of chromosome 6 and schizophrenia. However, significant threshold levels were not always achieved, and the chromosomal regions identified are large and different in different families. One way to decrease the problem of heterogeneity is to study a single extended pedigree. Here we report the analysis of a very large, previously undescribed pedigree from northern Sweden that includes 31 affected individuals. We typed 16 markers spanning 40 cM on the short arm of chromosome 6. Linkage analysis was performed only with the affected individuals. Suggestive lod scores (maximum 2.6) were obtained with markers on chromosome 6p23 in a single branch of the large pedigree indicating possible heterogeneity inside the family. A haplotype comprising markers from D6S309 to D6S1578 was found to segregate with the disease. This chromosomal region is included within a segment proposed to contain a susceptibility gene for schizophrenia by many other investigators. Our results thus give further support for a possible localization of a susceptibility locus for schizophrenia in 6p23 and help to narrow the candidate chromosomal region to the segment included between markers D6S309 and D6S1578. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:369–377, 1999. © 1999 Wiley-Liss, Inc.