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J. M. McGree J. A. Eccleston S. B. Duffull 《Journal of pharmacokinetics and pharmacodynamics》2009,36(2):101-123
We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional
nature of such models, differences in predicted responses are a consequence of different assumptions about how the models
interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques
have been explored in the literature where it was found that the sequential and FO approaches can produce biased results.
It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal
design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected
Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into
our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical
and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates
formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed
and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature.
We consider design for situations where all responses are continuous and extend this methodology to the case where a response
may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such
responses will offer little information about all parameters and hence a sequential optimization, in the form of product design
optimality, may yield near optimal designs. 相似文献
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1 240例女性生殖道支原体感染分析 总被引:23,自引:5,他引:18
目的 为了解生殖道支原体在晚期孕妇、育龄妇女、念珠菌性阴道炎和淋球菌性阴道炎患者中的感染状况。方法 采用套式聚合酶链反应技术,对962例晚期孕妇、85例育龄妇女、90例念珠菌性阴道炎和103例淋球菌性阴道炎患者的宫颈拭子标本进行了生殖道支原体检测。结果 在晚期孕妇、育龄妇女、念珠菌性阴道炎和淋球菌性阴道炎患者中生殖道支原体的检出率分别为4.16%、3.52%、11.1l%和13.59%。结论 生殖道支原体在晚期孕妇、育龄妇女、念珠菌性阴道炎和淋球菌性阴道炎妇女中均有一定的检出率。 相似文献
5.
G. Van Goethem J.-J. Martin A. Lfgren I. Dehaene P. Tack M. Van Zandycke D. Ververken C. Ceuterick C. Van Broeckhoven 《European journal of neurology》1997,4(5):476-484
We studied 14 patients from three unrelated Belgian pedigrees with a familial mitochondrial disorder and multiple deletions of mitochondrial DNA (mtDNA). In one family with an oculopharyngeal presentation there is a clear autosomal dominant inheritance. Progressive external ophthalmoplegia (PEO), “ragged red fibres” (RRF) and multiple deletions of mtDNA are common to all three families. Therefore a diagnosis of autosomal dominant progressive ophthalmoplegia with multiple deletions of mtDNA (adPEO) was made in one family at least. Our data confirm the previous observations that adPEO is a systemic disorder rather than a pure myopathy. In our pedigrees frequently associated features include axonal peripheral neuropathy, dysphagia, psychiatric illness, and sudden death. Mild ataxia, pes cavus and mitral valve prolapse with associated mitral insufficiency also occur. In some cases onset is atypical with neuropathy, adolescent onset myopathy or psychiatric illness. In such cases the common features of PEO and muscle weakness always complete the clinical phenotype later during the course of the disease. Biochemical studies on mitochondrial fractions prepared from one patient's muscle, revealed no abnormalities of respiratory chain enzyme activities. 相似文献
6.
Multiplex PCR analysis of in vivo-arising deletion mutations in the hprt gene of human T-lymphocytes
James C. Fuscoe Lisa J. Zimmerman Karen Harrington-Brock Martha M. Moore 《Environmental and molecular mutagenesis》1994,23(2):89-95
A multiplex polymerase chain reaction (PCR) procedure was adapted for the rapid and efficient evaluation of deletions of the hypoxanthine guanine phosphoribosyltransferase (hprt) gene in human T-lymphocytes. The hprt clonal assay was used to isolate in vivo-arising hprt-deficient T-cells from six healthy males. Mutant frequencies ranged from 9-27 × 10?6. Simple crude cellular extracts from 223 mutants were analyzed for hprt gene deletion. Sixteen (7.2%) were found to be due to total gene deletion and 22 (9.9%) were due to partial gene deletion. The relatively high frequency of total gene deletions was caused by replicate isolates of a single mutational event as shown by single-strand conformation polymorphism (SSCP) analysis of rearranged T-cell receptor (TCR)-γ genes. Eighteen of the 22 partial hprt gene deletion mutants were determined to be of independent origin based on a unique hprt mutation or SSCP-TCR-γ pattern. One-half (9/18) of the partial deletion mutants involved all or part of exon 4 alone, suggesting that this region of the hprt gene is prone to deletion. The small deletions effecting exon 1 (1 mutant), exon 2 (2 mutants), and exon 4 (6 mutants) would not have been detected by conventional Southern blot analysis and may represent a new, previously unrecognized class of mutations. The ready isolation of such intragenic deletions will allow the characterization of breakpoint junctions and may provide insights into the important processes of DNA breakage and rejoining. © 1994 Wiley-Liss, Inc. 相似文献
7.
Fotios A. Asimakopoulos Nicholas J. White Elisabeth P. Nacheva & Anthony R. Green 《British journal of haematology》1995,92(1):127-130
Deletions of chromosome 20q are associated with myeloid malignancies and have been previously shown to arise in a multipotent progenitor of both myeloid and B cells. However, B-cell differentiation from the abnormal progenitor was impaired. The CD40 antigen is a surface glycoprotein which is expressed in B cells and haemopoietic stem cells and is important for B-cell growth and development. Following the recent mapping of CD40 to chromosome 20q we sought to determine its position relative to 20q deletions. Analysis of lymphoblastoid cell lines carrying 20q deletions placed CD40 within a 19–21 cM interval which is almost coincidental with the common deleted region defined by previous analysis of patient samples. Our results raise the possibility that genetic alteration of this locus may contribute to the pathogenesis of myeloid disorders associated with 20q deletions. 相似文献
8.
Baccetti B Collodel G Estenoz M Manca D Moretti E Piomboni P 《Human reproduction (Oxford, England)》2005,20(10):2790-2794
BACKGROUND: Asthenozoospermia may sometimes be related to geneticstructural defects of the sperm tail detectable by transmissionelectron microscopy. Dysplasia of the fibrous sheath (DFS) isa genetic sperm defect, characterized by dysplastic developmentof the axonemal and periaxonemal cytoskeleton. We report thecase of an infertile man with normal sperm count and total spermimmotility in which dysplasia of the fibrous sheath, Akap3,Akap4 gene deletions, meiotic segregation of chromosomes 18,X and Y and Y microdeletions were investigated. METHODS: A 32-year-oldman with a 3-year history of primary infertility presented atour Regional Referral Center for Male Infertility. Family medicalhistory, lymphocyte karyotype, PCR analysis, physical examination,hormone assays and semen analysis were performed. RESULTS: Ultrastructuralsperm evaluation showed dysplasia of the fibrous sheath. Immunostainingof AKAP4 protein was negative in sperm tails. PCR analysis revealedintragenic deletions of the Akap3 and Akap4 genes. Fluorescencein situ hybridization on sperm showed a high frequency of XYdisomy. CONCLUSION: In this infertile patient, our results suggesta possible relationship between dysplasia of the fibrous sheath,partial deletions in the Akap3 and Akap4 genes and absence ofAKAP4 protein in the fibrous sheath. These findings, however,were not detected in another four patients with dysplasia ofthe fibrous sheath. Our results require future confirmatorymolecular analyses. 相似文献
9.
Brice Poreau Francis Ramond Radu Harbuz Véronique Satre Claire Barro Claire Vettier Véronique Adouard Julien Thevenon Pierre‐Simon Jouk Charles Coutton Klaus Dieterich 《American journal of medical genetics. Part A》2019,179(4):650-654
The AMME syndrome defined as the combination of Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis (AMME) is known to be a contiguous gene syndrome associated with microdeletions in the region Xq22.3q23. Recently, using exome sequencing, missense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, and elliptocytosis. In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome. In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array‐CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers. These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency. These cases reporting the smallest microdeletions encompassing AMMECR1 gene provide new evidence for involvement of AMMECR1 in the AMME phenotype and permit to discuss a phenotype related to AMMECR1 haploinsufficiency: developmental delay/intellectual deficiency, midface hypoplasia, midline defect, deafness, and short stature. 相似文献
10.
THE POTENTIAL USES OF GENOTYPING OF PLASMODIUMFALCIPARUMISOLATESBYTHENESTEDPOLYMERASECHAINREACTION 总被引:1,自引:0,他引:1
巢式PCR方法被应用于泰国疟区(Borai)恶性疟原虫的基因分型。应用特异的等位基因引物扩增了恶性疟原虫裂殖子表面蛋白1(MSP1)基因的1、4变异多态区。以凝胶电泳分析扩增的目的基因片段。结果表明:共分别检测出恶性疟原虫6个MAD20等位基因型、4个K1和1个RO33等位基因型。在9个月的流行季节,上述虫株的等位基因频率没有明显的改变,关存在较高程度的恶性疟原虫不同等位基因株的混合感染。本文进一步阐明了巢式PCR技术在疟疾流行病学上的应用前景及优点。 相似文献