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Ross Lazarus

Publications and source records attributed to Ross Lazarus.

At least 19 recordsLinked to original sources
PubMed2007

A new multimarker test for family-based association studies.

We propose a new multimarker test for family-based studies in candidate genes. We use simulations under different genetic models to assess the performance of competing testing strategies, characterized in this study as combinations of the following important factors: genes, statistical tests, tag single nucleotide polymorphisms (SNP) methods, number of tag SNPs and family designs. An ANOVA model is employed to provide descriptive summaries of the effects on power of the above-mentioned factors. We find that tag SNP methods, gene characteristics and family designs have minimal impact on the best testing strategy. The familywise error rate (FWER) controlling multiple comparison procedure and the new multimarker test offer the highest power followed by the asymptotic global haplotype test. Both the FWER and the multimarker test are invariant to family designs and gain power as we increase the number of tag SNPs. However, the performance of the global haplotype test is slightly degraded when analyzing larger numbers of tag SNPs. Within the framework of our study, the best strategy for family-based studies in candidate genes that emerged from our analysis is to use the FWER or the multimarker test and select 6-10 tag SNPs using any of the tag SNP methods considered. We confirm the conclusions of our study with an application to Alzheimer's disease data.

Alzheimer Disease↗
PubMed2006

GGtools: analysis of genetics of gene expression in bioconductor.

UNLABELLED: This paper reviews the central concepts and implementation of data structures and methods for studying genetics of gene expression with the GGtools package of Bioconductor. Illustration with a HapMap+expression dataset is provided. AVAILABILITY: Package GGtools is part of Bioconductor 1.9 (http://bioconductor.org). Open source with Artistic License.

Chromosome Mapping↗
PubMed2006

Pathologic outcome of laparoscopic and open radical prostatectomy.

OBJECTIVES: To compare the clinicopathologic data of 286 laparoscopic radical prostatectomies (LRPs) and 714 open radical prostatectomies (RRPs) performed at the Massachusetts General Hospital from 2001 to 2005. METHODS: A total of 1000 radical prostatectomy procedures were analyzed for prostate weight, pathologic stage, Gleason score, surgical margin status, and positive margin location. RESULTS: The mean patient age was 58.6 and 59.1 years for the LRP and RRP groups, respectively. The mean preoperative prostate-specific antigen level was 5.96 and 6.00 ng/mL, respectively. Clinical Stage T1c cancer was seen in 86.4% of the LRP and 90.5% of the RRP patients. Gleason score 7 or less disease was seen on biopsy in 97.5% of the LRP and 96.9% of the RRP patients. The average prostate weight was 46.8 g for LRP and 46.0 g for RRP. In the radical prostatectomy specimens, 94.4% of LRP and 93.3% of RRP patients had Gleason score 7 or less disease and 86.0% of LRP and 81.7% of RRP patients had pathologic Stage pT2 cancer. The rate of positive surgical margins was 15.0% and 17.4% for the LRP and RRP groups, respectively. The positive margins occurred mainly at the peripheral and apical regions in both groups. No significant difference was found in the preoperative variables or final pathologic findings between the two surgical groups. CONCLUSIONS: With similar case selection, LRP and RRP achieve similar pathologic outcomes.

Adult↗
PubMed2006

Genome-wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica.

BACKGROUND: Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma-related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans. METHODS: Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV(1)) and FEV(1)/ forced vital capacity (FVC; both pre-bronchodilator and post-bronchodilator) and BDR were performed in these eight families (pre-bronchodilator spirometry, n = 640; post-bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking. RESULTS: Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV(1) (post-bronchodilator) was found on chromosome 7q34-35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV(1)/FVC (pre-bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near-significant evidence of linkage to FEV(1)/FVC (post-bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV(1) on chromosomes 3q (pre-bronchodilator, LOD = 2.74) and 4q (post-bronchodilator, LOD = 2.66). CONCLUSIONS: In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV(1) on chromosome 7q34-35. In these families, FEV(1)/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.

Adolescent↗
PubMed2006

Distributed data processing for public health surveillance.

BACKGROUND: Many systems for routine public health surveillance rely on centralized collection of potentially identifiable, individual, identifiable personal health information (PHI) records. Although individual, identifiable patient records are essential for conditions for which there is mandated reporting, such as tuberculosis or sexually transmitted diseases, they are not routinely required for effective syndromic surveillance. Public concern about the routine collection of large quantities of PHI to support non-traditional public health functions may make alternative surveillance methods that do not rely on centralized identifiable PHI databases increasingly desirable. METHODS: The National Bioterrorism Syndromic Surveillance Demonstration Program (NDP) is an example of one alternative model. All PHI in this system is initially processed within the secured infrastructure of the health care provider that collects and holds the data, using uniform software distributed and supported by the NDP. Only highly aggregated count data is transferred to the datacenter for statistical processing and display. RESULTS: Detailed, patient level information is readily available to the health care provider to elucidate signals observed in the aggregated data, or for ad hoc queries. We briefly describe the benefits and disadvantages associated with this distributed processing model for routine automated syndromic surveillance. CONCLUSION: For well-defined surveillance requirements, the model can be successfully deployed with very low risk of inadvertent disclosure of PHI--a feature that may make participation in surveillance systems more feasible for organizations and more appealing to the individuals whose PHI they hold. It is possible to design and implement distributed systems to support non-routine public health needs if required.

Bioterrorism↗
PubMed2006

Extracting principal diagnosis, co-morbidity and smoking status for asthma research: evaluation of a natural language processing system.

BACKGROUND: The text descriptions in electronic medical records are a rich source of information. We have developed a Health Information Text Extraction (HITEx) tool and used it to extract key findings for a research study on airways disease. METHODS: The principal diagnosis, co-morbidity and smoking status extracted by HITEx from a set of 150 discharge summaries were compared to an expert-generated gold standard. RESULTS: The accuracy of HITEx was 82% for principal diagnosis, 87% for co-morbidity, and 90% for smoking status extraction, when cases labeled "Insufficient Data" by the gold standard were excluded. CONCLUSION: We consider the results promising, given the complexity of the discharge summaries and the extraction tasks.

Asthma↗
PubMed2006

Genetic association analysis of functional impairment in chronic obstructive pulmonary disease.

RATIONALE: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions. OBJECTIVES: To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms. METHODS: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test-replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study. RESULTS: The test-replication approach identified four genes-microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-beta binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-beta1 (TGFB1)-that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p < or = 0.03) and in LTBP4 (p < or = 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p < or = 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p < or = 0.04). Three SNPs in TGFB1 were associated with dyspnea (p < or = 0.002), one of which replicated in the family study (p = 0.02). CONCLUSIONS: Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV(1). These associations may identify genes in pathways important for COPD pathogenesis.

Aged↗
PubMed2006

Eotaxin polymorphisms and serum total IgE levels in children with asthma.

BACKGROUND: Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated with serum total IgE, blood eosinophil counts, and circulating eotaxin protein levels in several case-control asthma studies. Family-based association studies of CCL11 genetic variants have not been reported to date. OBJECTIVE: To evaluate 9 common CCL11 single nucleotide polymorphisms (SNPs) in nuclear families ascertained through patients with asthma participating in the Childhood Asthma Management Program study. METHODS: Single nucleotide polymorphism genotyping was performed by using minisequencing and probe hybridization platforms. Family-based association analysis for asthma and 4 asthma-related intermediate quantitative phenotypes was performed by using FBAT. RESULTS: One SNP, -384A>G, was associated with asthma among African American families (P = .01). CCL11 SNPs and haplotypes were not associated with asthma among white or Hispanic families. Two low-frequency alleles in strong pairwise linkage disequilibrium, -426C and IVS2+199A, were associated with lower serum total IgE levels (P = .0006 and P = .009, respectively) in white families, whereas 2 more common variants, -576C and g.4438C, were associated with higher IgE levels in African American families (P = .01-.04). Haplotype analysis in the white cohort provided additional evidence of association with serum total IgE, implicating 2 haplotypes. No single SNP or haplotype associations were observed with blood eosinophil levels, FEV(1), or airway responsiveness. CONCLUSION: These findings provide further evidence that genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma.

Adult↗
PubMed2006

Proxy respondents reliably assessed the quality of life of elective cardiac surgery patients.

BACKGROUND AND OBJECTIVE: The level of agreement between index and proxy respondents on assessment of health status of clinical cohorts is variable. There is limited information regarding agreement between cardiac surgery patients and their proxies, and levels of agreement examined across repeated measures. This study examined the level of agreement between index and proxy respondents' perceptions of the patient's health status prior to and following cardiac surgery. METHODS: A prospective, paired-respondent, repeated measures observational study of elective cardiac surgical patients and their next of kin, from the cardiac surgical unit of a tertiary hospital in Sydney, Australia. Health status domains were examined using the15D and SF-36 instruments at three points: prior to surgery, at hospital discharge, and at 6 months post discharge. RESULTS: Moderate to good level of agreement was noted for physical function (physical functioning, role functioning-physical, mobility, breathing, speech, hearing, usual activities, sexual activities) and some psychosocial dimensions (role functioning-emotional, sleeping, depression, mental health). Agreement was highest for presurgery and 6 months post discharge. Differences in scores were not clinically important. CONCLUSION: Proxy respondents can reliably assess the quality of life of a cardiac surgical patient using 15D or SF-36, particularly for domains reflecting physical function.

Cardiac Surgical Procedures↗
PubMed2006

Lack of association between genetic variation in 9 innate immunity genes and baseline CRP levels.

It is well-known that baseline levels of C-reactive protein (CRP) are an independent cardiovascular risk factor. We hypothesized that genetic variation with significant influence on CRP levels might be found in genes of the innate immunity system. We performed a candidate gene association study examining common single nucleotide polymorphisms in 9 innate immunity genes (CARD15, IRAK1, IRAK4, LBP, LY86, MEFV, TLR2, TLR4 and NFKB1) in relation to CRP levels. Seven hundred and seventeen subjects from the Women's Health Study population were studied: 359 and 358 samples with extremely low (<0.2 mg/liter) and high (>5 mg/liter) CRP levels, respectively. SNPs were identified from publicly available resequencing data, using a minor allele frequency threshold of >5% and a linkage disequilibrium (LD)-based strategy (r(2) > 0.8) to select 63 LD-independent markers. One non-synonymous SNP in TLR4 and two non-synonymous SNPs in CARD15, previously associated with atherosclerosis and Crohn's disease, respectively, were also studied. Univariate, haplotype and gene-gene interaction analyses all indicated no significant association with CRP levels. Although this work excludes a significant association of common SNPs in these nine genes with CRP levels, it is possible that rarer alleles in these genes, or variation in other innate immunity genes, could be associated with variation in CRP.

Atherosclerosis↗
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

Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer.

Chronic inflammation has been hypothesized to be a risk factor for prostate cancer. The Toll-like receptor 4 (TLR4) presents the bacterial lipopolysaccharide (LPS), which interacts with ligand-binding protein and CD14 (LPS receptor) and activates expression of inflammatory genes through nuclear factor-kappaB and mitogen-activated protein kinase signaling. A previous case-control study found a modest association of a polymorphism in the TLR4 gene [11381G/C, GG versus GC/CC: odds ratio (OR), 1.26] with risk of prostate cancer. We assessed if sequence variants of TLR4 were associated with the risk of prostate cancer. In a nested case-control design within the Health Professionals Follow-up Study, we identified 700 participants with prostate cancer diagnosed after they had provided a blood specimen in 1993 and before January 2000. Controls were 700 age-matched men without prostate cancer who had had a prostate-specific antigen test after providing a blood specimen. We genotyped 16 common (>5%) single nucleotide polymorphisms (SNP) discovered in a resequencing study spanning TLR4 to test for association between sequence variation in TLR4 and prostate cancer. Homozygosity for the variant alleles of eight SNPs was associated with a statistically significantly lower risk of prostate cancer (TLR4_1893, TLR4_2032, TLR4_2437, TLR4_7764, TLR4_11912, TLR4_16649, TLR4_17050, and TLR4_17923), but the TLR4_15844 polymorphism corresponding to 11381G/C was not associated with prostate cancer (GG versus CG/CC: OR, 1.01; 95% confidence interval, 0.79-1.29). Six common haplotypes (cumulative frequency, 81%) were observed; the global test for association between haplotypes and prostate cancer was statistically significant (chi(2) = 14.8 on 6 degrees of freedom; P = 0.02). Two common haplotypes were statistically significantly associated with altered risk of prostate cancer. Inherited polymorphisms of the innate immune gene TLR4 are associated with risk of prostate cancer.

Adult↗
PubMed2005

T-bet polymorphisms are associated with asthma and airway hyperresponsiveness.

RATIONALE: T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR. OBJECTIVES: To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association. METHODS: Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels. MAIN RESULTS: We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR. CONCLUSIONS: These data suggest that T-bet variation contributes to airway responsiveness in asthma.

Adolescent↗
PubMed2005

Extended haplotype in the tumor necrosis factor gene cluster is associated with asthma and asthma-related phenotypes.

RATIONALE: Tumor necrosis factor is a proinflammatory cytokine found in increased concentrations in asthmatic airways. The TNF-alpha (TNF) and lymphotoxin-alpha (LTA) genes belong to the TNF gene superfamily located within the human major histocompatibility complex on chromosome 6p in a region repeatedly linked to asthma. The TNF position -308 and LTA NcoI polymorphisms are believed to influence TNF transcription and secretion, respectively. OBJECTIVES: This study sought to determine whether polymorphisms in TNF or LTA, or in TNF-LTA haplotypes, are associated with asthma and asthma phenotypes. METHODS: We genotyped the TNF -308 and LTA NcoI polymorphisms, and two other haplotype-tagging polymorphisms in the TNF and LTA genes, in 708 children with mild to moderate asthma enrolled in the Childhood Asthma Management Program and in their parents. Using an extension of the family-based association tests in the PBAT program, each polymorphism was tested for association with asthma, age at onset of asthma, and time series data on baseline FEV(1) % predicted, postbronchodilator FEV(1) % predicted, body mass index, and log of PC(20). MEASUREMENTS AND MAIN RESULTS: Although no associations were found for the individual single-nucleotide polymorphisms, the haplotype analysis found the LTA NcoI_G/LTA 4371T/TNF -308G/TNF 1078G haplotype to be associated with asthma and with all five phenotype groups. CONCLUSIONS: We conclude that it is unlikely that the TNF -308 or LTA NcoI polymorphisms influence asthma susceptibility individually, but that this haplotype of variants may be functional or may be in linkage disequilibrium with other functional single-nucleotide polymorphisms.

Asthma↗
PubMed2005

Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma.

BACKGROUND: Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. Signal transducer and activator of transcription 3 is a transcription factor latent in the cytoplasm; the gene (STAT3) is activated by a wide range of cytokines, and may play a role in lung development and asthma pathogenesis. METHODS: We genotyped six single nucleotide polymorphisms (SNPs) in the STAT3 gene in a cohort of 401 Caucasian adult asthmatics. The associations between each SNP and forced expiratory volume in 1 second (FEV1), as a percent of predicted, at the baseline exam were tested using multiple linear regression models. Longitudinal analyses involving repeated measures of FEV1 were conducted with mixed linear models. Haplotype analyses were conducted using imputed haplotypes. We completed a second association study by genotyping the same six polymorphisms in a cohort of 652 Caucasian children with asthma. RESULTS: We found that three polymorphisms were significantly associated with baseline FEV1: homozygotes for the minor alleles of each polymorphism had lower FEV1 than homozygotes for the major alleles. Moreover, these associations persisted when we performed an analysis on repeated measures of FEV1 over 8 weeks. A haplotypic analysis based on the six polymorphisms indicated that two haplotypes were associated with baseline FEV1. Among the childhood asthmatics, one polymorphism was associated with both baseline FEV1 and the repeated measures of FEV1 over 4 years. CONCLUSION: Our results indicate that genetic variants in STAT3, independent of asthma treatment, are determinants of FEV1 in both adults and children with asthma, and suggest that STAT3 may participate in inflammatory pathways that have an impact on level of lung function.

Adult↗
PubMed2005

Lung function in type 2 diabetes: the Normative Aging Study.

BACKGROUND: Cross-sectional studies have noted that subjects with diabetes have lower lung function than non-diabetic subjects. We conducted this analysis to determine whether diabetic subjects have different rates of lung function change compared with non-diabetic subjects. METHODS: We conducted a nested case-control analysis in 352 men who developed diabetes and 352 non-diabetic subjects in a longitudinal observational study of aging in men. We assessed lung function among cases and controls at three time points: Time0, prior to meeting the definition of diabetes; Time1, the point when the definition of diabetes was met; and Time2, the most recent follow-up exam. RESULTS: Cases had lower forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) at all time points, even with adjustment for age, height, weight, and smoking. In multiple linear regression models adjusting for relevant covariates, there were no differences in rates of FEV1 or FVC change over time between cases and controls. CONCLUSIONS: Men who are predisposed to develop diabetes have decreased lung function many years prior to the diagnosis, compared with men who do not develop diabetes. This decrement in lung function remains after the development of diabetes. We postulate that mechanisms involved in the insulin resistant state contribute to the diminished lung function observed in our subjects.

Adult↗