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Elizabeth R Hauser

Publications and source records attributed to Elizabeth R Hauser.

24 records · Page 2Linked to original sources
PubMed2003

Accounting for linkage in family-based tests of association with missing parental genotypes.

In studies of complex diseases, a common paradigm is to conduct association analysis at markers in regions identified by linkage analysis, to attempt to narrow the region of interest. Family-based tests for association based on parental transmissions to affected offspring are often used in fine-mapping studies. However, for diseases with late onset, parental genotypes are often missing. Without parental genotypes, family-based tests either compare allele frequencies in affected individuals with those in their unaffected siblings or use siblings to infer missing parental genotypes. An example of the latter approach is the score test implemented in the computer program TRANSMIT. The inference of missing parental genotypes in TRANSMIT assumes that transmissions from parents to affected siblings are independent, which is appropriate when there is no linkage. However, using computer simulations, we show that, when the marker and disease locus are linked and the data set consists of families with multiple affected siblings, this assumption leads to a bias in the score statistic under the null hypothesis of no association between the marker and disease alleles. This bias leads to an inflated type I error rate for the score test in regions of linkage. We present a novel test for association in the presence of linkage (APL) that correctly infers missing parental genotypes in regions of linkage by estimating identity-by-descent parameters, to adjust for correlation between parental transmissions to affected siblings. In simulated data, we demonstrate the validity of the APL test under the null hypothesis of no association and show that the test can be more powerful than the pedigree disequilibrium test and family-based association test. As an example, we compare the performance of the tests in a candidate-gene study in families with Parkinson disease.

Algorithms↗
PubMed2003

Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients.

Complete DiGeorge syndrome is a fatal condition in which infants have no detectable thymus function. The optimal treatment for the immune deficiency of complete DiGeorge syndrome has not been determined. Safety and efficacy of thymus transplantation were evaluated in 12 infants with complete DiGeorge syndrome who had less than 20-fold proliferative responses to phytohemagglutinin. All but one had fewer than 50 T cells/mm3. Allogeneic postnatal cultured thymus tissue was transplanted. T-cell development was followed by flow cytometry, lymphocyte proliferation assays, and T-cell receptor Vbeta (TCRBV) repertoire evaluation. Of the 12 patients, 7 are at home 15 months to 8.5 years after transplantation. All 7 survivors developed T-cell proliferative responses to mitogens of more than 100 000 counts per minute (cpm). By one year after transplantation, 6 of 7 patients developed antigen-specific proliferative responses. The TCRBV repertoire showed initial oligoclonality that progressed to polyclonality within a year. B-cell function developed in all 3 patients tested after 2 years. Deaths were associated with underlying congenital problems. Risk factors for death included tracheostomy, long-term mechanical ventilation, and cytomegalovirus infection. Adverse events in the first 3 months after transplantation included eosinophilia, rash, lymphadenopathy, development of CD4-CD8- peripheral T cells, elevated serum immunoglobulin E (IgE), and possible pulmonary inflammation. Adverse events related to the immune system occurring more than 3 months after transplantation included thrombocytopenia in one patient and hypothyroidism and alopecia in one other patient. Thymic transplantation is efficacious, well tolerated, and should be considered as treatment for infants with complete DiGeorge syndrome.

Child↗
PubMed2003

Effects of covariates: a summary of Group 5 contributions.

This report summarizes the contributions of Genetic Analysis Workshop 13 (GAW13) related to the use of covariates in genetic analysis. Seven papers are summarized, five of which analyzed the Framingham Heart Study Data, and two the simulated data. Five papers examined the role of covariates in linkage analysis, using a variety of statistical approaches including affected sibling pair analysis, conditional logistic regression, and variance components methods. One paper examined the impact of covariates on family-based association analysis. In each of these papers, the detection of genetic effects could be influenced by the incorporation of covariates. The final paper examined the role of transmission ratio distortion in the analysis of complex traits and the role of covariates in the variability in transmission ratio distortion. While each paper takes a different approach to the genetic analysis of complex traits, a common thread running through each is that the inclusion of covariates can have a substantial impact on the results of the analysis. Care must be taken to understand how the covariates are being used in each analysis, what assumptions are being made, and how these assumptions might affect the results and their interpretation. Finally, the results of Group 5 studies show that inclusion of covariates can increase the power to detect genes for complex traits, and has the potential to advance an understanding of the role of genes in these complex traits.

Cardiovascular Diseases↗
PubMed2003

Design of the Genetics of Early Onset Cardiovascular Disease (GENECARD) study.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death and a leading cause of disability in the developed world. Early onset (premature) coronary artery disease (EOCAD) is known to have a particularly strong genetic component. However, the actual genes leading to this increased risk of CAD remain obscure. METHODS: The primary goal of the Genetics of Early Onset Cardiovascular Disease (GENECARD) study is to perform a genetic linkage study in 920 families with at least 1 sibling pair having EOCAD. The study sites include a US network of 15 cardiology practices and 5 additional sites located in Europe and the United States. We propose to identify chromosomal regions associated with increased susceptibility to EOCAD in this large sample of affected sibling pairs and nuclear families, where EOCAD is defined on the basis of having acute coronary syndrome (unstable angina or myocardial infarction), a revascularization procedure, or a positive functional imaging study at or before the age of 50 years in men or 55 years in women. To identify which genomic regions and genes are associated with increased susceptibility to EOCAD, we will use a comprehensive strategy comprising genomic screening, fine mapping, candidate gene analysis, and family-based association studies. RESULTS: Herein we describe the clinical characteristics, family history, and risk factor profiles of the 1168 members from 438 nuclear families included in the first, exploratory analysis. Analysis of the study population revealed a strong concordance of known cardiac risk factors among affected sibling pairs. There was significant concordance (P <. 01) among siblings with EOCAD for presence of diabetes (78% concordance), dyslipoproteinemia (67%), obesity (63%), and hypertension (56%). This level of concordance of risk factors among siblings might be expected, given the significant genetic components demonstrated for these metabolic susceptibility traits. However, there was also substantial sibling pair concordance (P <.01) for smoking history (74%), regular alcohol consumption (81%), and sedentary lifestyle (63%), environmental traits without known inherited predisposition. CONCLUSIONS: Analyses such as these will have implications for stratifying populations for the statistical analysis of the genome scan and on the choice of covariates for the follow-up studies of the initial genome screen analysis.

Adult↗