Biomedical subjects

Daniel Franke

Publications and source records attributed to Daniel Franke.

6 recordsLinked to original sources

PubMed2006

Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system.

OBJECT: Important central nervous system (CNS) manifestations in patients with hereditary hemorrhagic telangiectasia (HHT) include arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Hereditary hemorrhagic telangiectasia is caused by germline mutations of two genes: ENG (HHT Type 1) and ACVRL1 (HHT Type 2). The ENG gene variations have been associated with the formation of intracranial aneurysms. The authors studied whether sequence variations in ACVRL1 or ENG are associated with the development of clinically sporadic arteriovenous dysplasias and aneurysms of the CNS. METHODS: The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis. One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers. The authors identified a statistically significant association between the IVS3 -35A/T polymorphism in intron 3 of the ACVRL1 gene and the development of AVMs and DAVFs (p = 0.004; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.19-2.51; after adjustments for age and sex), but not aneurysms (crude OR 0.82; 95% CI 0.55-1.18). CONCLUSIONS: The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.

Activin Receptors, Type II↗

PubMed2005

Haseman-Elston weighted by marker informativity.

In the Haseman-Elston approach the squared phenotypic difference is regressed on the proportion of alleles shared identical by descent (IBD) to map a quantitative trait to a genetic marker. In applications the IBD distribution is estimated and usually cannot be determined uniquely owing to incomplete marker information. At Genetic Analysis Workshop (GAW) 13, Jacobs et al. [BMC Genet 2003, 4(Suppl 1):S82] proposed to improve the power of the Haseman-Elston algorithm by weighting for information available from marker genotypes. The authors did not show, however, the validity of the employed asymptotic distribution. In this paper, we use the simulated data provided for GAW 14 and show that weighting Haseman-Elston by marker information results in increased type I error rates. Specifically, we demonstrate that the number of significant findings throughout the chromosome is significantly increased with weighting schemes. Furthermore, we show that the classical Haseman-Elston method keeps its nominal significance level when applied to the same data. We therefore recommend to use Haseman-Elston with marker informativity weights only in conjunction with empirical p-values. Whether this approach in fact yields an increase in power needs to be investigated further.

Chromosomes, Human, Pair 4↗

PubMed2005

Haplotype-sharing analysis for alcohol dependence based on quantitative traits and the Mantel statistic.

Haplotype-based methods have become increasingly popular in the last decade because shared lengths in haplotypes can be used for disease localization. In this contribution, we propose a novel linkage-based haplotype-sharing approach for quantitative traits based on the class of Mantel statistics which is closely related to the weighted pair-wise correlation statistic. Because these statistics are known to be liberal, we propose a permutation test to evaluate significance. We applied the Mantel statistic to the autosomal data from the genome-wide scan of the Collaborative Study on the Genetics of Alcoholism with the Affymetrix Genotype 10 K array that was provided for the Genetic Analysis Workshop 14. Four regions on chromosome 4, 8, 16, and 20 showed p-values less than 0.005 with a minimum p-value of < 0.0001 on chromosome 16 (tsc0520638 at 72.8 cM). Three of these four regions located on chromosome 4, 16, and 20 have been reported previously in the Genetic Analysis Workshop 11.

Alcoholism↗

PubMed2005

On confidence intervals for genotype relative risks and attributable risks from case parent trio designs for candidate-gene studies.

Scherag et al. [Hum Hered 2002;54:210-217] recently proposed point estimates and asymptotic as well as exact confidence intervals for genotype relative risks (GRRs) and the attributable risk (AR) in case parent trio designs using single nucleotide polymorphism (SNP) data. The aim of this study was the investigation of coverage probabilities and bias in estimates if the marker locus is not identical to the disease locus. Using a variety of parameter constellations, including marker allele frequencies identical to and different from the SNP at the disease locus, we performed an analytical study to quantify the bias and a Monte-Carlo simulation study for quantifying both bias and coverage probabilities. No bias was observed if marker and trait locus coincided. Two parameters had a strong impact on coverage probabilities of confidence intervals and bias in point estimates if they did not coincide: the linkage disequilibrium (LD) parameter delta and the allele frequency at the marker SNP. If marker allele frequencies were different from the allele frequencies at the functional SNP, substantial biases occurred. Further, if delta between the marker and the disease locus was lower than the maximum possible delta, estimates were also biased. In general, biases were towards the null hypothesis for both GRRs and AR. If one GRR was not increased, as e.g. in a recessive genetic model, biases away from the null could be observed. If both GRRs were in identical directions and if both were substantially larger than 1, the bias always was towards the null. When applying point estimates and confidence intervals for GRRs and AR in candidate gene studies, great care is needed. Effect estimates are substantially biased towards the null if either the allele frequencies at the marker SNP and the true disease locus are different or if the LD between the marker SNP and the disease locus is not at its maximum. A bias away from the null occurs only in uncommon study situations; it is small and can therefore be ignored for applications.

Confidence Intervals↗

PubMed2005

Weighting affected sib pairs by marker informativity.

For the analysis of affected sib pairs (ASPs), a variety of test statistics is applied in genomewide scans with microsatellite markers. Even in multipoint analyses, these statistics might not fully exploit the power of a given sample, because they do not account for incomplete informativity of an ASP. For meta-analyses of linkage and association studies, it has been shown recently that weighting by informativity increases statistical power. With this idea in mind, the first aim of this article was to introduce a new class of tests for ASPs that are based on the mean test. To take into account how much informativity an ASP contributes, we weighted families inversely proportional to their marker informativity. The weighting scheme is obtained by use of the de Finetti representation of the distribution of identity-by-descent values. We derive the limiting distribution of the weighted mean test and demonstrate the validity of the proposed test. We show that it can be much more powerful than the classical mean test in the case of low marker informativity. In the second part of the article, we propose a Monte Carlo simulation approach for evaluating significance among ASPs. We demonstrate the validity of the simulation approach for both the classical and the weighted mean test. Finally, we illustrate the use of the weighted mean test by reanalyzing two published data sets. In both applications, the maximum LOD score of the weighted mean test is 0.6 higher than that of the classical mean test.

Alleles↗

PubMed2004

Antibodies from a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer's disease.

The neuropathology of Alzheimer's disease(AD) is characterized by the accumulation of amyloid peptide Abeta in the brain derived from proteolytic cleavage of the amyloid precursor protein (APP). Vaccination of mice with plasmid DNA coding for the human Abeta42 peptide together with low doses of preaggregated peptide induced antibodies with detectable titers after only 2 weeks. One serum was directed against the four aminoterminal amino acids DAEF and differs from previously described ones. Both immune sera and monoclonal antibodies solubilized preformed aggregates of Abeta42 in vitro and recognized amyloid plaques in brain sections of mice transgenic for human APP. Passive immunization of transgenic AD mice caused a significant and rapid reduction in brain amyloid plaques within 24 h. The combined DNA peptide vaccine may prove useful for active immunization with few inoculations and low peptide dose which may prevent the recently described inflammatory reactions inpatients. The monoclonal antibodies are applicable for passive immunization studies and may lead to a therapy of AD.

Alzheimer Disease↗