Biomedical subjects

Amy Murphy

Publications and source records attributed to Amy Murphy.

8 recordsLinked to original sources

PubMed2006

Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica.

Serum total immunoglobulin E (IgE) is a critical intermediate phenotype of allergic diseases. Although total IgE exhibits sexual dimorphism in humans (with males demonstrating higher IgE than females), the molecular basis of this difference is unknown. A genome-wide scan of 380 short-tandem repeat (STR) markers was performed in eight extended pedigrees of asthmatic children (n=655) from the Central Valley of Costa Rica. Genome-wide linkage analysis of total IgE was performed by variance component models. Among all subjects, only one genomic region (chromosome 7p15) showed modest evidence of linkage to total IgE (LOD=1.60). In contrast, a sex-stratified analysis revealed distinct genetic architectures of total IgE in males and females and identified significant linkage to total IgE on a novel male-specific locus on chromosome 20p12 (LOD=3.63 at 36 cM). Genotyping of additional STRs on chromosome 20 resulted in improved evidence for linkage (LOD=3.75 at 33 cM) and a 1.5 LOD-unit support interval for the linkage peak between 26 and 38 cM. Three polymorphisms in two genes on chromosome 20p12 (JAG1 and ANKRD5) were then found to be associated with total IgE in 420 nuclear families of Costa Rican children with asthma. Two of these polymorphisms (in JAG1) were significantly associated with total IgE in families of boys (n=264) but not in families of girls (n=156) with asthma. JAG1 is a hematopoetic cell growth factor that may regulate normal B-cell development. This is the first demonstration of a possible genetic basis for differences in total IgE between sexes.

Adolescent↗

PubMed2006

Impact of psoriasis on health-related quality of life decreases over time: an 11-year prospective study.

Although psoriasis typically affects patients for many years, studies quantifying impairment in health-related quality of life (HRQOL) owing to psoriasis over long periods are lacking. This study, which interviewed patients independent of psoriasis care, investigates change in the impact of psoriasis on HRQOL over 11 years and factors associated with change among 484 patients using the Impact of Psoriasis Questionnaire (IPSO). We determined changes in the impact of psoriasis on HRQOL using a psychometrically optimized version of the IPSO. In 1993, the patients were 53+/-11.4 years and 61.8% males. From 1993 to 2004, impact on most social aspects of HRQOL remained stable, but concerns related to physical appearance decreased (e.g., 36-13%, P = 0.001). Over 11 years, the proportion of patients with low overall impact of psoriasis increased significantly (43-53%, P < 0.001). Mean IPSO scores (range 0-22) decreased by one-fifth (5-4, P < 0.001). At follow-up, patients reporting poor health had mean improvement in HRQOL about three times greater than those in good health (P < 0.05). In this large cohort interviewed independent of treatments and psoriasis status, impact of psoriasis on HRQOL decreases over time. For chronic diseases, HRQOL is best measured over time and independently of seeking treatment.

Adult↗

PubMed2006

Comparison of warfarin versus aspirin for the prevention of recurrent stroke or death: subgroup analyses from the Warfarin-Aspirin Recurrent Stroke Study.

BACKGROUND AND PURPOSE: We performed a combination of prespecified and exploratory subgroup analyses to detect any treatment differences among various baseline subgroups in the Warfarin-Aspirin Recurrent Stroke Study (WARSS) cohort. METHODS: The WARSS compared the efficacy of adjusted-dose warfarin (INR 1.4-2.8) to aspirin (325 mg/day) for recurrent ischemic stroke or death within 2 years. The effect of warfarin and aspirin was compared among prespecified and exploratory subgroups with respect to sociodemographic and vascular risk factors, stroke subtype, arterial territory, and infarct topography. Hazard ratios and 95% confidence intervals comparing warfarin to aspirin were calculated using Cox proportional hazards models. Differences in hazard ratios were tested using interaction terms. RESULTS: No treatment differences between warfarin and aspirin were found across multiple prespecified subgroups. In a multivariate model, warfarin was associated with greater hazard among patients with moderate stroke severity (HR 1.63, 95% CI 1.005-2.64, p = 0.047) and a greater benefit among those with posterior circulation location without brainstem infarction (HR 0.54, 95% CI 0.33-0.88, p = 0.013). In post-hoc analyses of the cryptogenic subgroup, warfarin was associated with worse outcomes among patients with moderate stroke severity and better outcomes among those without baseline hypertension or with posterior circulation infarcts sparing the brainstem. CONCLUSIONS: In the WARSS, the majority of subgroup analyses showed no benefit of warfarin over aspirin. Warfarin benefit was limited to brainstem-sparing posterior circulation infarcts and select cryptogenic stroke subgroups. Pending future clinical trial evidence to the contrary, antiplatelets are recommended for survivors of noncardioembolic stroke.

Aged↗

PubMed2006

Coalition-based approaches for addressing environmental issues in childhood asthma.

Outdoor air pollution and the indoor environment have been shown to cause or exacerbate childhood asthma. Allies Against Asthma coalitions implemented a broad range of activities to reduce or remediate indoor exposure to asthma environmental triggers for children with asthma including education and trigger remediation, physician and other health care provider education, and policy efforts to improve air quality in homes and schools. Outdoor environmental triggers were addressed through programs to increase education and awareness and efforts to change policies related to environmental conditions. Implementation of such efforts was complicated by the lack of safe and affordable housing and the amount of time and resources necessary to address policy change. Keys to success included promoting coordination and partnerships among coalition members, implementation of consistent messages, and building a broad and unified voice for policy change.

Adolescent↗

PubMed2005

Genomic screening in family-based association testing.

Due to the recent gains in the availability of single-nucleotide polymorphism data, genome-wide association testing has become feasible. It is hoped that this additional data may confirm the presence of disease susceptibility loci, and identify new genetic determinants of disease. However, the problem of multiple comparisons threatens to diminish any potential gains from this newly available data. To circumvent the multiple comparisons issue, we utilize a recently developed screening technique using family-based association testing. This screening methodology allows for the identification of the most promising single-nucleotide polymorphisms for testing without biasing the nominal significance level of our test statistic. We compare the results of our screening technique across univariate and multivariate family-based association tests. From our analyses, we observe that the screening technique, applied to different settings, is fairly consistent in identifying optimal markers for testing. One of the identified markers, TSC0047225, was significantly associated with both the ttth1 (p = 0.004) and ttth1-ttth4 (p = 0.004) phenotype(s). We find that both univariate- and multivariate-based screening techniques are powerful tools for detecting an association.

Family↗

PubMed2005

Comparison of linkage and association strategies for quantitative traits using the COGA dataset.

Genome scans using dense single-nucleotide polymorphism (SNP) data have recently become a reality. It is thought that the increase in information content for linkage analysis as a result of the denser scans will help refine previously identified linkage regions and possibly identify new regions not identifiable using the sparser, microsatellite scans. In the context of the dense SNP scans, it is also possible to consider association strategies to provide even more information about potential regions of interest. To circumvent the multiple-testing issues inherent in association analysis, we use a recently developed strategy, implemented in PBAT, which screens the data to identify the optimal SNPs for testing, without biasing the nominal significance level. We compare the results from the PBAT analysis to that of quantitative linkage analysis on chromosome 4 using the Collaborative Study on the Genetics of Alcoholism data, as released through Genetic Analysis Workshop 14.

Alcoholism↗

PubMed2005

Genomic screening and replication using the same data set in family-based association testing.

The Human Genome Project and its spin-offs are making it increasingly feasible to determine the genetic basis of complex traits using genome-wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome-wide family-based association studies, using single SNPs or haplotypes, can identify associations that achieve genome-wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease-susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease-susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype-tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome-wide significance, as population-based designs do.

Asthma↗

PubMed2004

A family-based association test for repeatedly measured quantitative traits adjusting for unknown environmental and/or polygenic effects.

We propose a family-based association test, FBAT-PC, for studies with quantitative traits that are measured repeatedly. The traits may be influenced by partially or completely unknown factors that may vary for each measurement. Using generalized principal component analysis, FBAT-PC amplifies the genetic effects of each measurement by constructing an overall phenotype with maximal heritability. Analytically, and in the simulation studies, we compare FBAT-PC with standard methodology and assess both the heritability of the overall phenotype and the power of FBAT-PC. Compared to univariate analysis, FBAT-PC achieves power gains of up to 200%. Applications of FBAT-PC to an osteoporosis study and to an asthma study show the practical relevance of FBAT-PC. FBAT-PC has been implemented in the software package PBAT and is freely available at http://www.biostat.harvard.edu/~clange/default.htm.

Journal Article↗