Tutorial in biostatistics: spline smoothing with linear mixed models

The semi-parametric regression achieved via penalized spline smoothing can be expressed in a linear mixed models framework. This allows such models to be fitted using standard mixed models software routines with which many biostatisticians are familiar. Moreover, the analysis of complex correlated data structures that are a hallmark of biostatistics, and which are typically analysed using mixed models, can now incorporate directly smoothing of the relationship between an outcome and covariates. In this paper we provide an introduction to both linear mixed models and penalized spline smoothing, and describe the connection between the two. This is illustrated with three examples, the first using birth data from the U.K., the second relating mammographic density to age in a study of female twin-pairs and the third modelling the relationship between age and bronchial hyperresponsiveness in families. The models are fitted in R (a clone of S-plus) and using Markov chain Monte Carlo (MCMC) implemented in the package WinBUGS.     

Power and robustness of linkage tests for quantitative traits in general pedigrees

There are numerous statistical methods for quantitative trait linkage analysis in human studies. An ideal such method would have high power to detect genetic loci contributing to the trait, would be robust to non-normality in the phenotype distribution, would be appropriate for general pedigrees, would allow the incorporation of environmental covariates, and would be appropriate in the presence of selective sampling. We recently described a general framework for quantitative trait linkage analysis, based on generalized estimating equations, for which many current methods are special cases. This procedure is appropriate for general pedigrees and easily accommodates environmental covariates. In this report, we use computer simulations to investigate the power and robustness of a variety of linkage test statistics built upon our general framework. We also propose two novel test statistics that take account of higher moments of the phenotype distribution, in order to accommodate non-normality. These new linkage tests are shown to have high power and to be robust to non-normality. While we have not yet examined the performance of our procedures in the context of selective sampling via computer simulations, the proposed tests satisfy all of the other qualities of an ideal quantitative trait linkage analysis method.     

Combined Linkage and Association Tests in Mx

Statistical methods aimed at the detection of genes for quantitative traits suffer from two problems: (i) when a linkage approach is employed, relatively large sample sizes are usually required; and (ii) when an association approach is employed, effects of population stratification may blur genuine locus-trait associations. The variance components method proposed by Fulker et al. (1999) addressed both these problems; it is statistically powerful because it involves a combined analysis of linkage and association and can include information from multiplex families, which reduces the overall amount of necessary individual genotypes. In addition, it includes an explicit test for the presence of spurious association. After a brief illustration of the various ways in which population stratification may affect locus-trait associations, the implementation in Mx (Neale, 1997) of the method as proposed by Fulker et al. (1999) is discussed and illustrated. In addition, an extension to this method is proposed that allows the use of (variable) sibship sizes greater than two, the estimation of additive and dominance association effects, and the use of multiple alleles. These extensions can be implemented when parental genotypes are available or unavailable.     

Multicomponent donor apheresis in the Americas

Multicomponent donor apheresis utilizes apheresis technology to collect combinations of red blood cells, platelets and plasma units. The United States has embraced this technology to the greatest extent of the countries in the Americas. As whole blood and apheresis collection have increased, so have the donor deferrals based on potential exposure to infectious agents. However, hemoglobin/hematocrit deferrals still remain the largest upfront deferral for volunteer donors. As the technology is refined in future years, multicomponent donor apheresis may become the predominant method of collecting blood products from donors.     

The pros and cons of change in individuals with eating disorders: a broader perspective

OBJECTIVE: The goals of the current study were to develop a questionnaire measuring the pros and cons of eating disorder symptoms and to explore the themes endorsed by different eating disorder groups. METHOD: Participants recruited from an eating disorder volunteer register and an outpatient clinic completed the Pros and Cons of Eating Disorders scale (P-CED). Principal components analyses (PCA) were performed to validate the factorial structure of the original items and to explore the factorial structure of the new items. Planned comparisons were used to compare P-CED scores between diagnostic groups. RESULTS: PCA indicated a 10-factor solution for the original Pros and Cons of Anorexia Nervosa scale (P-CAN) items and a 4-factor solution for the new items. Participants with anorexia nervosa (AN) scored significantly higher than participants with bulimia nervosa (BN) on five of the P-CED subscales but there were no significant differences between the two AN subtypes. CONCLUSION: The P-CED is a useful tool for identifying the positive and negative aspects of eating disorders that can be targeted in treatment or used as an outcome measure in research.     

系统生物学与中药有效组分的研究

本文阐述了将系统生物学引入到中医药研究中的必要性与指导意义,并以中药有效组分与整体受试系统相互作用作为先导研究范例,阐述了在病证结合、方证对应的中医理论指导下,运用现代技术实现中医药现代化的理念与实施方案.指出系统生物学研究的是一个生物系统中所有组分的构成及其在特定条件下这些组分之间的相互关系.人体是一个非线性复杂系统,其研究要求尽可能地获得每个层次的信息并将它们进行整合,因而必须采用以系统论和还原论相结合为特色的复杂性科学研究方法.中医药学主动运用与其匹配的系统生物学理论与方法学指导科研实践初步显示了其可行性与必要性,并且在某些领域有了很大突破,尤其在中药有效组分对机体的整体作用及其机理研究方面已充分体现了其科学性、合理性.     

基于药物代谢酶和转运蛋白的中药方剂配伍规律研究

药物代谢酶和转运蛋白是决定药物体内过程的关键因素,底物对它们的抑制或诱导作用是药物联合应用时产生药动学相互作用的主要机制。作为复杂化学成分组合体的中药及其有效成分也表现出对药物代谢酶和转运蛋白的抑制或诱导作用,并且中药在配伍应用时也产生了对药效物质体内过程的影响。由此认为,这种作用可能也是中药在按照传统君臣佐使配伍原则组成方剂时发挥增效解毒作用的一个重要机制,在体内直接作用物质层面上研究整合药物代谢酶和转运蛋白活性的方剂配伍规律,对于指导有效组分配伍将具有重要意义。     

CHEMICAL,BIOLOGICAL AND IMMUNOLOGICAL CHARACTERIZATION OF SEPARATED ELECTROPHORETIC COMPONENTS OF HUMAN CHORIONIC SOMATOMAMMOTROPIN (HCS)

Purified HCS preparations often show heterogeneity when assayed by electrophoresis, although they may be considered homogeneous according to other criteria (N-terminal amino acid analysis, gel filtration and ultracentrifugation patterns, etc.). Using DEAE-cellulose chromatography, the two main components corresponding to various degrees of hormone amidation were separated. The deamidation kinetic of the electrophoretically slower migrating component was studied and found to be sensitive to temperature and, to a lesser extent, to pH. Denaturing agents strongly increased the deamidation rate, while no effect was found by raising the ionic strength. No difference was evident between the two components and the parent hormone when compared (on a weight basis) in a specific HCS radioimmunoassay system. Even the precipitin reaction in agar gel with an anti-human growth hormone (HGH) serum did not show variations in cross-reactivity versus HGH. Moreover, groups of guinea pigs immunized with the single HCS components, gave antibodies reacting identically with the components and the parent HCS. The prolactin-like activity of the two components differed when determined by the pigeon crop-sac assay: the slower migrating component proved to be less active than the more deamidated one. On the other hand, the activity in two different radioreceptor assays (employing membranes from rabbit mammary gland and rat ventral prostate) was greater for the faster migrating component.