Specialty: Pediatric and Adult Pulmonary Medicine
Massachusetts General Hospital for Children
Brigham and Women’s Hospital
181 Longwood Avenue
Boston, MA 02115
The following is a list of recent publications for which this Partners Asthma Center physician has been cited as an author in PubMed databases. Study abstracts have been provided for your convenience.
Lake, S. L., H. Lyon, et al. (2003). "Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous." Hum Hered 55(1): 56-65.
In the study of complex traits, the utility of linkage analysis and single marker association tests can be limited for researchers attempting to elucidate the complex interplay between a gene and environmental covariates. For these purposes, tests of gene-environment interactions are needed. In addition, recent studies have indicated that haplotypes, which are specific combinations of nucleotides on the same chromosome, may be more suitable as the unit of analysis for statistical tests than single genetic markers. The difficulty with this approach is that, in standard laboratory genotyping, haplotypes are often not directly observable. Instead, unphased marker phenotypes are collected. In this article, we present a method for estimating and testing haplotype-environment interactions when linkage phase is potentially ambiguous. The method builds on the work of Schaid et al.  and is applicable to any trait that can be placed in the generalized linear model framework. Simulations were run to illustrate the salient features of the method. In addition, the method was used to test for haplotype-smoking exposure interaction with data from the Childhood Asthma Management Program.
Tantisira, K. G., D. M. Systrom, et al. (2002). "An elevated breathing reserve index at the lactate threshold is a predictor of mortality in patients with cystic fibrosis awaiting lung transplantation." Am J Respir Crit Care Med 165(12): 1629-33.
The proportion of cystic fibrosis (CF) patients dying while on the lung transplant wait list remains high; identification of such patients remains difficult. The breathing reserve index (BRI = minute ventilation/maximal voluntary ventilation) at the lactate threshold (LT) is a predictor of a pulmonary mechanical limit to incremental exercise. We hypothesized that an elevated BRI at the LT in patients with CF awaiting lung transplantation would be a predictor of wait list mortality. Forty-five consecutive patients with CF completed cardiopulmonary exercise testing as part of their pretransplant assessment. We evaluated BRI at LT, baseline demographic characteristics, pulmonary function, and other exercise parameters via Cox proportional hazards modeling. Fifteen patients died while awaiting transplant. Twenty one were transplanted, and nine still awaited transplantation. Relative risks from the multivariate model included (95% confidence interval in parentheses) BRI at LT, 17.52 (2.45-123.97); resting Pa(CO(2)), 1.29 (1.10-1.49); resting Pa(O(2)), 0.97 (0.90-1.05); and forced expiratory volume at one second as a percent of predicted, 1.19 (1.05-1.34). BRI at LT not only provided the highest point estimate of risk for wait list mortality but also identified a physiologically significant threshold value (0.70 or more) for those at risk. This measurement may allow improved timing of listing for transplantation, including consideration for living donor transplantation.
Stanchina, M. L., K. G. Tantisira, et al. (2002). "Association of lung perfusion disparity and mortality in patients with cystic fibrosis awaiting lung transplantation." J Heart Lung Transplant 21(2): 217-25.
BACKGROUND: The risk of death for patients with end-stage cystic fibrosis awaiting lung transplantation remains high and most patients succumb to respiratory failure. This study was conducted to evaluate the usefulness of ventilation-perfusion scintillation scans, obtained during the pre-transplant period, to identify patterns that predict prognosis while on the waiting list. These patterns were compared with other pulmonary physiologic markers of ventilation and perfusion obtained from pulmonary function and cardiopulmonary exercise tests. METHODS: From November 1990 to January 1999, 46 patients with cystic fibrosis were listed for bilateral lung transplantation. Fourteen (30.4%) died while waiting for a transplant (Group 1), whereas 32 were transplanted successfully or remain alive and waiting (Group 2). Mean arterial blood gas values, Brasfield radiograph scores, cardiopulmonary exercise data and the degree of scintillation scan abnormalities between lungs were compared for each group. RESULTS: Mean survival for Group 1 was 10.2 +/- 1.7 months, and for Group 2 was 23.5 +/- 3.0 months (p < 0.001). The right upper lung zone was the most severely affected segment. The Cox proportional hazards model revealed an increased perfusion disparity and resting hypercapnia as the main predictors of death while on the transplant list. The Kaplan-Meier analysis indicated greater survival for the groups with <30% disparity between lungs on the pre-transplant scintillation scans. CONCLUSIONS: The results suggest that severe, unilateral perfusion abnormalities seen on scintillation scans in patients with cystic fibrosis are associated with an increased risk of dying while on the lung transplant waiting list and may be helpful in identifying patients who should be considered for early or living-donor transplantation.
Baron, R. M., L. J. Palmer, et al. (2002). "DNA sequence variants in epithelium-specific ETS-2 and ETS-3 are not associated with asthma." Am J Respir Crit Care Med 166(7): 927-32.
Epithelium-specific ETS-2 and ETS-3 are transcription factors that have been proposed as asthma candidate genes. To investigate the association of sequence variants in these genes with asthma, we conducted a case-control association analysis in a sample of 311 white subjects with asthma and 177 white subjects without asthma. Common polymorphisms in these genes were detected by sequencing DNA from 32 cell lines obtained from Coriel (Camden, NJ). Seven noncoding or synonymous single-nucleotide polymorphisms were detected: three in epithelium-specific ETS-2 and four in epithelium-specific ETS-3. Subjects were genotyped at all loci by mass spectroscopy. To ensure the suitability of our control subjects, we also genotyped subjects at 49 unlinked polymorphisms evenly distributed throughout the autosomes and found no evidence of population stratification. Logistic regression adjusted for age and sex suggested a weak association of one epithelium-specific ETS-2 polymorphism with asthma diagnosis (odds ratio = 1.89, 95% confidence interval = 1.13-3.18, p = 0.02). Total serum immunoglobulin E and FEV1 predicted levels were not associated with any of the polymorphisms. Extended haplotyping indicated linkage disequilibrium in these genes; however, no association or epistatic interaction was found. This study suggests that epithelium-specific ETS-2 and ETS-3 genes are unlikely to contain polymorphic loci that have a major impact on asthma susceptibility in our population.
Tantisira, K. G. and S. T. Weiss (2001). "Complex interactions in complex traits: obesity and asthma." Thorax 56 Suppl 2: ii64-73.
Tantisira, K. G. and S. T. Weiss (2001). "Childhood infections and asthma: at the crossroads of the hygiene and Barker hypotheses." Respir Res 2(6): 324-7.
The hygiene hypothesis states that childhood asthma develops as a result of decreased exposure to infectious agents during infancy and early childhood. This results in the persistence of the neonatal T helper lymphocyte 2 immunophenotype, thereby predisposing the child to atopic disease. While multiple studies support the hygiene hypothesis in asthma ontogeny, the evidence remains inconclusive; multiple other environmental exposures in early childhood also alter predisposition to asthma. Moreover, the current paradigm for asthma development extends far beyond simple childhood environmental exposures to include fetal development, genetic predisposition, and interactions of the developmental state and genetics with the environment.