Rebecca A Betensky
Rebecca Betensky
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Chair of the Department of Biostatistics
Professor of Biostatistics
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Professional overview
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Prior to NYU, Dr. Betensky was Professor of Biostatistics at the Harvard T.H. Chan School of Public Health. She was director of the Harvard Catalyst (Clinical and Translational Science Award) Biostatistics Program; director of the Data and Statistics Core for the Massachusetts Alzheimer’s Disease Research Center; and director of the Biostatistics Neurology Core at Massachusetts General Hospital. Previously, she was the Biostatistics Program Leader for the Dana-Farber/Harvard Cancer Center.
Dr. Betensky’s research focuses on methods for the analysis of censored and truncated outcomes and covariates, which frequently arise from the subsampling of cohort studies. She has a long-time interest in clinical trials, and has written on the evaluation of biomarkers and the use and interpretation of p-values. She has collaborated extensively in studies in neurologic diseases, and serves as statistical editor for Annals of Neurology.
Dr. Betensky was awarded, and directed for 15 years, an NIH T32 training program in neurostatistics and neuroepidemiology for pre- and post-doctoral students in biostatistics and epidemiology and for clinician-scientists. She previously directed Harvard’s Biostatistics programs to promote and support diversity at all levels in the field of quantitative public health. She was also a member of the BMRD Study Section for review of NIH statistical methodology grants; on committees for the Institute of Medicine; and a co-chair of the technical advisory committee for the scientific registry of transplant recipients.
Dr. Betensky an elected Fellow of the American Statistical Association and of the International Statistical Institute, and is a past recipient of the Spiegelman Award from the American Public Health Association. She currently serves as a member of the Board of Scientific Counselors for Clinical Science and Epidemiology at the National Cancer Institute.
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Education
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AB, Mathematics, Harvard University, Cambridge, MAPhD, Statistics, Stanford University, Stanford, CA
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Areas of research and study
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BiologyBiostatisticsNeuroepidemiologyNeurologyNeurostatisticsTranslational science
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Publications
Publications
A computationally tractable multivariate random effects model for clustered binary data
AbstractCoull, B. A., Houseman, E. A., & Betensky, R. A. (n.d.).Publication year
2006Journal title
BiometrikaVolume
93Issue
3Page(s)
587-599AbstractWe consider a multivariate random effects model for clustered binary data that is useful when interest focuses on the association structure among clustered observations. Based on a vector of gamma random effects and a complementary log-log link function, the model yields a likelihood that has closed form, making a frequentist approach to model-fitting straightforward. This closed form yields several advantages over existing methods, including easy inspection of model identifiability and straightforward adjustment for nonrandom ascertainment of subjects, such as that which occurs in family studies of disease aggregation. We use the proposed model to analyse two different binary datasets concerning disease outcome data from a familial aggregation study of breast and ovarian cancer in women and loss of heterozygosity outcomes from a brain tumour study.A pseudolikelihood approach for simultaneous analysis of array comparative genomic hybridizations
AbstractEngler, D. A., Mohapatra, G., Louis, D. N., & Betensky, R. A. (n.d.).Publication year
2006Journal title
BiostatisticsVolume
7Issue
3Page(s)
399-421AbstractDNA sequence copy number has been shown to be associated with cancer development and progression. Array-based comparative genomic hybridization (aCGH) is a recent development that seeks to identify the copy number ratio at large numbers of markers across the genome. Due to experimental and biological variations across chromosomes and hybridizations, current methods are limited to analyses of single chromosomes. We propose a more powerful approach that borrows strength across chromosomes and hybridizations. We assume a Gaussian mixture model, with a hidden Markov dependence structure and with random effects to allow for intertumoral variation, as well as intratumoral clonal variation. For ease of computation, we base estimation on a pseudolikelihood function. The method produces quantitative assessments of the likelihood of genetic alterations at each clone, along with a graphical display for simple visual interpretation. We assess the characteristics of the method through simulation studies and analysis of a brain tumor aCGH data set. We show that the pseudolikelihood approach is superior to existing methods both in detecting small regions of copy number alteration and in accurately classifying regions of change when intratumoral clonal variation is present. Software for this approach is available at http://www.biostat.harvard.edu/∼betensky/papers.html.Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: Correlation with EGFR status, tumor grade, and survival
AbstractMizoguchi, M., Betensky, R. A., Batchelor, T. T., Bernay, D. C., Louis, D. N., & Nutt, C. L. (n.d.).Publication year
2006Journal title
Journal of Neuropathology and Experimental NeurologyVolume
65Issue
12Page(s)
1181-1188AbstractDiffuse astrocytic gliomas are the most common human glial tumors with glioblastoma being the most malignant form. Epidermal growth factor receptor (EGFR) gene amplification is one of the most common genetic changes in glioblastoma and can lead to the activation of various downstream signaling molecules, including STAT3, MAPK, and AKT. In this study, we investigated the activation status of these 3 signaling molecules as well as wild-type (EGFRwt) and mutant (EGFRvIII) EGFR in 82 malignant astrocytic gliomas (55 glioblastomas and 27 anaplastic astrocytomas) using immunohistochemistry. The presence of EGFRwt, but not EGFRvIII, immunopositivity correlated significantly with prevalent EGFR gene amplification in glioblastomas. STAT3 and AKT activation correlated significantly with EGFR status, although the correlation for p-STAT3 was attributed exclusively to EGFRvIII. The distribution of these 3 activated molecules varied significantly with tumor grade; although activation of STAT3 was essentially identical between anaplastic astrocytomas and glioblastomas, an increase in the activation of MAPK and AKT appeared to correlate with the progression of anaplastic astrocytoma to glioblastoma. Finally, activated STAT3 and AKT were marginally predictive of improved and worse prognosis, respectively. Taken together, these findings begin to elucidate the interrelationship between these signaling pathways in astrocytic gliomas in vivo.AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling
AbstractRiemenschneider, M. J., Betensky, R. A., Pasedag, S. M., & Louis, D. N. (n.d.).Publication year
2006Journal title
Cancer ResearchVolume
66Issue
11Page(s)
5618-5623AbstractAberrant AKT (protein kinase B) signaling is common in many cancers, including glioblastoma. Current models suggest that AKT acts directly, or indirectly via the TSC complex, to activate the mammalian target of rapamycin (mTOR) as the main downstream mediator of AKT signaling. mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We aimed to delineate these pathways in a primarily in situ manner using immunohistochemistry in a panel of 29 glioblastomas, emphasizing the histologie distribution of molecular changes. Within individual tumors, increased expression levels of p-TSC2, p-mTOR, P-4E-BP1, p-S6K, p-S6, and p-STAT3 were found in regions defined by elevated AKT activation. However, only TSC2, S6K, and S6 activation levels correlated significantly with AKT activation and clustered together in multidimensional scaling analyses. Ki-67 proliferation indices were significantly elevated in p-AKT-overexpressing regions, whereas expression of the apoptosis marker cleaved caspase 3 was generally low and not significantly different between the regions. These findings provide the first in vivo evidence for a close correlation between AKT and TSC2 phosphorylation levels in glioblastoma. Moreover, they suggest that downstream p-AKT effects are primarily mediated by S6 kinase signaling, thus enhancing proliferation rather than inhibiting apoptosis.Analysis of co-aggregation of cancer based on registry data
AbstractMatthews, A. G., Betensky, R. A., Anton-Culver, H., Bowen, D., Griffin, C., Isaacs, C., Kasten, C., Mineau, G., Nayfield, S., Schildkraut, J., Strong, L., Weber, B., & Finkelstein, D. M. (n.d.).Publication year
2006Journal title
Community GeneticsVolume
9Issue
2Page(s)
87-92AbstractObjective: An exploratory analysis of co-aggregation of cancers using registry-based data. Methods: We utilized sibships from over 18,000 families who had been recruited to the NCI-sponsored multi-institutional Cancer Genetics Network. The analysis assesses co-aggregation at the individual and family level and adjusts for ascertainment. Results: We found statistically significant familial co-aggregation of lung cancer with pancreatic (adjusted p < 0.001), prostate (adjusted p < 0.003), and colorectal cancers (adjusted p = 0.004). In addition, we found significant familial co-aggregation of pancreatic and colorectal cancers (adjusted p = 0.018), and co-aggregation of hematopoietic and (non-ovarian) gynecologic cancers (adjusted p = 0.01). Conclusion: This analysis identified familial aggregation of cancers for which a genetic component has yet to be established.Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease
AbstractGarcia-Alloza, M., Robbins, E. M., Zhang-Nunes, S. X., Purcell, S. M., Betensky, R. A., Raju, S., Prada, C., Greenberg, S. M., Bacskai, B. J., & Frosch, M. P. (n.d.).Publication year
2006Journal title
Neurobiology of DiseaseVolume
24Issue
3Page(s)
516-524AbstractTransgenic mice carrying disease-linked forms of genes associated with Alzheimer disease often demonstrate deposition of the β-amyloid as senile plaques and cerebral amyloid angiopathy. We have characterized the natural history of β-amyloid deposition in APPswe/PS1dE9 mice, a particularly aggressive transgenic mouse model generated with mutant transgenes for APP (APPswe: KM594/5NL) and PS1 (dE9: deletion of exon 9). Ex vivo histochemistry showed Aβ deposition by 4 months with a progressive increase in plaque number up to 12 months and a similar increase of Aβ levels. In vivo multiphoton microscopy at weekly intervals showed increasing β-amyloid deposition as CAA and plaques. Although first appearing at an early age, CAA progressed at a significantly slower rate than in the Tg2576 mice. The consistent and early onset of β-amyloid accumulation in the APPswe/PS1dE9 model confirms its utility for studies of biochemical and pathological mechanisms underlying β-amyloid deposition, as well as exploring new therapeutic treatments.Effects of unmeasured heterogeneity in the linear transformation model for censored data
AbstractZhang, B., Li, Y., & Betensky, R. A. (n.d.).Publication year
2006Journal title
Lifetime Data AnalysisVolume
12Issue
2Page(s)
191-203AbstractWe investigate the effect of unobserved heterogeneity in the context of the linear transformation model for censored survival data in the clinical trials setting. The unobserved heterogeneity is represented by a frailty term, with unknown distribution, in the linear transformation model. The bias of the estimate under the assumption of no unobserved heterogeneity when it truly is present is obtained. We also derive the asymptotic relative efficiency of the estimate of treatment effect under the incorrect assumption of no unobserved heterogeneity. Additionally we investigate the loss of power for clinical trials that are designed assuming the model without frailty when, in fact, the model with frailty is true. Numerical studies under a proportional odds model show that the loss of efficiency and the loss of power can be substantial when the heterogeneity, as embodied by a frailty, is ignored.Expression of oligodendroglial and astrocytic lineage markers in diffuse gliomas: Use of YKL-40, ApoE, ASCL1, and NKX2-2
AbstractRousseau, A., Nutt, C. L., Betensky, R. A., Iafrate, A. J., Han, M., Ligon, K. L., Rowitch, D. H., & Louis, D. N. (n.d.).Publication year
2006Journal title
Journal of Neuropathology and Experimental NeurologyVolume
65Issue
12Page(s)
1149-1156AbstractThe phenotypic heterogeneity of astrocytic and oligodendroglial tumor cells complicates establishing accurate diagnostic criteria, and lineage-specific markers would facilitate diagnosis of glioma subtypes. Based on data from the literature and from expression microarrays, we selected molecules relevant to gliogenesis and glial lineage specificity and then used immunohistochemistry to assess expression of these molecules in 55 diffuse gliomas, including 8 biphasic oligoastrocytomas, 21 oligodendrogliomas (all with 1p/19qloss), 21 astrocytomas, and 5 glioblastomas. For the astrocytic lineage markers (GFAP, YKL-40, and ApoE), GFAP expression was significantly higher in the astrocytic component of oligoastrocytomas compared with the oligodendroglial part; similar patterns were detected for YKL-40 and ApoE, although the differences were not significant. GFAP, YKL-40, and ApoE reliably distinguished grade II-III oligodendrogliomas from grade II-IV astrocytomas (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Among the oligodendroglial lineage markers (Olig2, Sox10, ASCL1, and NKX2-2), ASCL1 and NKX2-2 displayed significantly different immunostaining between oligodendrogliomas and astrocytomas (p = 0.017 and 0.004, respectively), but none clearly differentiated between the 2 glial populations of oligoastrocytomas. In addition to GFAP, therefore, YKL-40, ApoE, ASCL1, and NKX2-2 represent promising tumor cell markers to distinguish oligodendrogliomas from astrocytomas.Family History of Diabetes Is a Major Determinant of Endothelial Function
AbstractGoldfine, A. B., Beckman, J. A., Betensky, R. A., Devlin, H., Hurley, S., Varo, N., Schonbeck, U., Patti, M. E., & Creager, M. A. (n.d.).Publication year
2006Journal title
Journal of the American College of CardiologyVolume
47Issue
12Page(s)
2456-2461AbstractObjectives: We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family history (FH) of diabetes and assessed its relationship with insulin resistance and atherosclerosis risk factors. Background: Atherosclerosis is frequently present when type 2 diabetes (T2D) is first diagnosed. Endothelial dysfunction contributes to atherogenesis. Methods: Oral glucose tolerance and brachial artery flow-mediated, endothelium-dependent vasodilation (EDV) were assessed in 38 nondiabetic subjects; offspring of two parents with T2D (FH+) or with no first-degree relative with diabetes (FH-). Results: Although fasting glucose was higher in FH+ than FH- (5.3 ± 0.1 mmol/l vs. 4.9 ± 0.1 mmol/l, p < 0.03), glycemic burden assessed as 2-h or area-under-the-curve glucose after glucose load or glycosylated hemoglobin (HbA1c), and measures of insulin sensitivity or inflammation did not differ. Brachial artery flow-mediated EDV was reduced in FH+ (7.1 ± 0.9% vs. 11.7 ± 1.6%, p < 0.02), with no difference in nitroglycerin-induced endothelium-independent vasodilatation. In the combined cohort, only FH+ (r2 = 0.12, p < 0.02) and HbA1c (r2 = 0.14, p < 0.02) correlated with EDV. Insulin resistance, assessed by tertile of homeostasis model assessment of insulin resistance (HOMA-IR), was associated with impaired endothelium-dependent vasodilatation in FH- (p < 0.03, analysis of variance), but not in FH+, as even the most insulin-sensitive FH+ offspring had diminished endothelial function. In multiple regression analysis, including established cardiac risk factors, blood pressure and lipids, HbA1c, and HOMA-IR, FH remained a significant determinant of EDV (p = 0.04). Conclusions: Bioavailability of nitric oxide is lower in persons with a strong FH of T2D. Glycemic burden, even in the nondiabetic range, can contribute to endothelial dysfunction. Abnormalities of endothelial function may contribute to atherosclerosis before development of overt diabetes.Feature-specific penalized latent class analysis for genomic data
AbstractHouseman, E. A., Coull, B. A., & Betensky, R. A. (n.d.).Publication year
2006Journal title
BiometricsVolume
62Issue
4Page(s)
1062-1070AbstractGenomic data are often characterized by a moderate to large number of categorical variables observed for relatively few subjects. Some of the variables may be missing or noninformative. An example of such data is loss of heterozygosity (LOH), a dichotomous variable, observed on a moderate number of genetic markers. We first consider a latent class model where, conditional on unobserved membership in one of k classes, the variables are independent with probabilities determined by a regression model of low dimension q. Using a family of penalties including the ridge and LASSO, we extend this model to address higher-dimensional problems. Finally, we present an orthogonal map that transforms marker space to a space of "features" for which the constrained model has better predictive power. We demonstrate these methods on LOH data collected at 19 markers from 93 brain tumor patients. For this data set, the existing unpenalized latent class methodology does not produce estimates. Additionally, we show that posterior classes obtained from this method are associated with survival for these patients.Glioma test array for use with formalin-fixed, paraffin-embedded tissue: Array comparative genomic hybridization correlates with loss of heterozygosity and fluorescence in situ hybridization
AbstractMohapatra, G., Betensky, R. A., Miller, E. R., Carey, B., Gaumont, L. D., Engler, D. A., & Louis, D. N. (n.d.).Publication year
2006Journal title
Journal of Molecular DiagnosticsVolume
8Issue
2Page(s)
268-276AbstractArray-based comparative genomic hybridization (aCGH) is a powerful, high-throughput tool for whole genome analysis. Until recently, aCGH could only be reproducibly performed on frozen tissue samples and with significant tissue amounts. For brain tumors however, paraffin-embedded tissue blocks from small stereotactic biopsies may be the only tissue routinely available. The development of methods to analyze formalin-fixed, paraffin-embedded (FFPE) material therefore has the potential to impact molecular diagnosis in a significant way. To this end, we constructed a BAC array representing chromosomes 1, 7, 19, and X because 1p/19q deletion and EGFR gene amplification provide clinically relevant information for glioma diagnosis. We also optimized a two-step labeling procedure using an amine-modified nucleotide for generating aCGH probes. Using this approach, we analyzed a series of 28 FFPE oligodendroglial tumors for alterations of chromosomes 1, 7, and 19. We also independently assayed these tumors for 1p/19q deletion by fluorescence in situ hybridization and by loss of heterozygosity analyses. The concordance between aCGH, standard loss of heterozygosity and fluorescence in situ hybridization was nearly 100% for the chromosomes analyzed. These results suggest that aCGH could offer an improved molecular diagnostic approach for gliomas because of its ability to detect clinically relevant molecular alterations in small FFPE specimens.Hospital volume versus outcome: An unusual example of bivariate association
AbstractBetensky, R. A., Christian, C. K., Gustafson, M. L., Daley, J., & Zinner, M. J. (n.d.).Publication year
2006Journal title
BiometricsVolume
62Issue
2Page(s)
598-604AbstractThe Leapfrog Group, a consortium of more than 100 large employers, purchasing coalitions, and states that collectively provide health insurance to more than 33 million people, convened in 2000 with the goal of using market forces to improve the quality of healthcare. The resulting Leapfrog initiative suggested selective referral of complex procedures to high-volume hospitals and set volume thresholds for five procedures. This was based on the hypothesis that low-volume hospitals have higher mortality, which can be viewed in simplified statistical terms as the hypothesis that the binomial p is a decreasing function of n. The analysis of the correlation between hospitals' standardized mortality ratios (SMR, i.e., the ratio of observed to expected deaths) and hospitals' procedural volumes is revealing about the volume/mortality hypothesis. This presents an unusual pedagogic example in which the detection of correlation in the presence of nonlinear dependence is of primary interest, and thus the Pearson correlation is ideally suited. The frequently preferred nonparametric measures of bivariate association are inappropriate as they are unable to discriminate between correlation and dependence.Immunoglobulin gene rearrangement analysis in cerebrospinal fluid of patients with lymphoproliferative processes
AbstractBaehring, J. M., Hochberg, F. H., Betensky, R. A., Longtine, J., & Sklar, J. (n.d.).Publication year
2006Journal title
Journal of the Neurological SciencesVolume
247Issue
2Page(s)
208-216AbstractObjective: To determine the sensitivity and specificity of clonal immunoglobulin heavy chain gene rearrangement (IGHR) analysis in the distinction of benign and malignant lymphoproliferative diseases. Methods: A retrospective analysis was conducted of patients in whom a malignant lymphoproliferative process was suspected. Cells of CSF samples were collected by centrifugation, resuspended in 100 μl of the supernatant and boiled. A 10 μl aliquot of this lysate served as template for semi-nested polymerase chain reaction using variable and joining region consensus primers. PCR products were analyzed by polyacrylamide gel electrophoresis. Cytopathological diagnosis and flow cytometry results were recorded. Sensitivity and specificity of IGHR analysis, cytopathology and flow cytometry were calculated. Results: Eleven patients (12 specimens) had involvement of leptomeninges at the time of lumbar puncture. Another 25 cases (27 specimens) had normal CSF findings or were diagnosed with benign lymphoproliferative conditions. Sensitivity of CSF cytopathology, flow cytometry and IGHR analysis were 0.27 [95% confidence interval 0.06, 0.61], 0.1 [0.003, 0.45] and 0.58 [0.28, 0.85]. Specificity was 1 [0.86, 1], 0.95 [0.77, 1.0] and 0.85 [0.66, 0.96]. Interpretation: IGHR analysis appears to be a useful addition to morphological and flow cytometry analysis of cerebrospinal fluid in the evaluation of CNS lymphoproliferative processes.Kinetics of cerebral amyloid angiopathy progression in a transgenic mouse model of Alzheimer disease
AbstractRobbins, E. M., Betensky, R. A., Domnitz, S. B., Purcell, S. M., Garcia-Alloza, M., Greenberg, C., Rebeck, G. W., Hyman, B. T., Greenberg, S. M., Frosch, M. P., & Bacskai, B. J. (n.d.).Publication year
2006Journal title
Journal of NeuroscienceVolume
26Issue
2Page(s)
365-371AbstractCerebral amyloid angiopathy (CAA), the deposition of cerebrovascular β-amyloid (Aβ) in the walls of arterial vessels, has been implicated in hemorrhagic stroke and is present in most cases of Alzheimer disease. Previous studies of the progression of CAA in humans and animal models have been limited to the comparison of pathological tissue from different brains at single time points. Our objective was to visualize in real time the initiation and progression of CAA in Tg2576 mice by multiphoton microscopy through cranial windows. Affected vessels were labeled by methoxy-X04, a fluorescent dye that selectively binds cerebrovascular β-amyloid and plaques. With serial imaging sessions spaced at weekly intervals, we were able to observe the earliest appearance of CAA in leptomeningeal arteries as multifocal deposits of band-like Aβ. Over subsequent imaging sessions, we were able to identify growth of these deposits (propagation), as well as appearance of new bands (additional initiation events). Statistical modeling of the data suggested that as the extent of CAA progressed in this vascular bed, there was increased prevalence of propagation over initiation. During the early phases of CAA development, the overall pathology burden progressed at a rate of 0.35% of total available vessel area per day (95% confidence interval, 0.3-0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions.Methods to classify familial relationships in the presence of laboratory errors, without parental data
AbstractZhang, B., & Betensky, R. A. (n.d.).Publication year
2006Journal title
Human GeneticsVolume
119Issue
6Page(s)
642-648AbstractWe consider the problem of accurate classification of family relationship in the presence of laboratory error without parental data. We first propose an adjusted version of the test statistic proposed by Ehm and Wagner based on the summation over a large number of genetics markers. We then propose use of the Bayes factor as a classification rule. We prove theoretically that the Bayes factor is the optimal classification rule in that the total classification error is minimized. We show via simulations that both the adjusted Ehm and Wagner method and Bayes factor classification rule reduce misclassification errors, and that the Bayes factor classification rule is robust against under-estimation or over-estimation of laboratory errors. For monozygotic twins versus dizygotic twins, the correct classification rate of the Bayes rule is over 99%. For full-siblings versus half-siblings, the Bayes factor classification rule generally outperforms Ehm and Wagner's method (in Am J Hum Genet 62:181-188, 1998, especially when full-sibling proportion is high.Outcomes in a series of 103 retroperitoneal sarcomas
AbstractPierie, J. P., Betensky, R. A., Choudry, U., Willett, C. G., Souba, W. W., & Ott, M. J. (n.d.).Publication year
2006Journal title
European Journal of Surgical OncologyVolume
32Issue
10Page(s)
1235-1241AbstractAims: To report the effect on outcome of selection in patients receiving intra-operative electron beam radiation (IOERT) and external beam radiation therapy (EBRT). Methods: One hundred and three patients treated for primary RS were studied. Median follow-up was 27 months. Clinical presentation, tumor characteristics, and treatment methods were analyzed to determine impact on survival and recurrence and if selection was occurring. Results: Mean age was 55 ± 17 years. Mean tumor size was 15 ± 6 cm and 88 were high-grade. Complete gross tumor resection (CR) occurred in 62 patients and improved survival vs. both debulking (p = 0.0005) and biopsy (p < 0.0001). The 5- and 10-year survival rates were 62% and 52% for those with CR vs. 29% and 20% after incomplete resection. Among the 62 CR patients, there was selection to receive additional EBRT ± IOERT in patients with high-grade tumors (p = 0.005) and/or microscopically positive margins (p = 0.011). In these high-risk patients there was a trend for IOERT to further augment survival vs. EBRT alone and to increase the time to both local and distant recurrences (p = 0.036). Conclusions: Complete gross resection is the primary form of curative treatment for retroperitoneal sarcomas. Selection led to patients with high-risk tumors receiving additional radiation therapy. There appears to be a beneficial effect of IOERT plus EBRT in these high-risk patients after complete tumor resection.Analysis of clonal immunoglobulin heavy chain rearrangements in ocular lymphoma
AbstractBaehring, J. M., Androudi, S., Longtine, J. J., Betensky, R. A., Sklar, J., Foster, C. S., & Hochberg, F. H. (n.d.).Publication year
2005Journal title
CancerVolume
104Issue
3Page(s)
591-597AbstractBACKGROUND. The morphologic diagnosis of primary and metastatic intraocular lymphoma (IOL) was made difficult by the paucicellular specimens with fragile populations of lymphocytes retrieved through pars plana vitrectomy (PPV). The analysis of immunoglobulin heavy chain (IgH) gene rearrangements (AIGHR) was used as an adjunct to cytopathology and flow cytometry in systemic lymphoma. In IOL, the sensitivity and specificity of AIGHR are unknown. METHODS. The authors reviewed the clinical records of patients who underwent PPV for suspicion of IOL at the Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary (Boston, MA) between 2000 and 2002. AIGHR was performed as a routine diagnostic test on cell lysates isolated from < 0.5 mL of vitreous fluid. The authors used seminested polymerase chain reaction (PCR) with consensus primers for the VDJ-region of the IgH gene. PCR products were analyzed by polyacrylamide gel electrophoresis. RESULTS. Thirty patients (37 specimens) with chronic vitritis and 17 patients (23 specimens) with IOL were included. The specificity of vitreous fluid cytopathology, flow cytometry, and AIGHR was 1.0, and the sensitivity values were 0.24, 0.36, and 0.64, respectively. AIGHR was negative in two patients for whom cytopathology or flow cytometry revealed the diagnosis of lymphoma. Clonal IGHR was found in four specimens classified as negative for lymphoma based on cytopathology and flow cytometry. CONCLUSIONS. AIGHR supplemented cytopathology and flow cytometry to increase the diagnostic yield in IOL.Analysis of familial aggregation in the presence of varying family sizes
AbstractMatthews, A. G., Finkelstein, D. M., & Betensky, R. A. (n.d.).Publication year
2005Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
54Issue
5Page(s)
847-862AbstractFamily studies are frequently undertaken as the first step in the search for genetic and/or environmental determinants of disease. Significant familial aggregation of disease is suggestive of a genetic aetiology for the disease and may lead to more focused genetic analysis. Of course, it may also be due to shared environmental factors. Many methods have been proposed in the literature for the analysis of family studies. One model that is appealing for the simplicity of its computation and the conditional interpretation of its parameters is the quadratic exponential model. However, a limiting factor in its application is that it is not reproducible, meaning that all families must be of the same size. To increase the applicability of this model, we propose a hybrid approach in which analysis is based on the assumption of the quadratic exponential model for a selected family size and combines a missing data approach for smaller families with a marginalization approach for larger families. We apply our approach to a family study of colorectal cancer that was sponsored by the Cancer Genetics Network of the National Institutes of Health. We investigate the properties of our approach in simulation studies. Our approach applies more generally to clustered binary data.Cell-surface MuSK self-association: A crucial role for the putative signal sequence
AbstractBianchetta, M. J., Betensky, R. A., & Cohen, J. B. (n.d.).Publication year
2005Journal title
BiochemistryVolume
44Issue
49Page(s)
16229-16238AbstractThe receptor tyrosine kinase MuSK plays a crucial role-both as a signaling molecule and structurally-in the process of clustering nicotinic acetylcholine receptors at the neuromuscular junction. Immunofluorescence microscopy of transiently transfected fibroblasts has been used to visualize the cell-surface distribution of MuSK, which is found in discrete, punctate clusters. This distribution does not result from targeting of MuSK to identified plasma membrane subdomains, and MuSK's association with itself is specific, as MuSK clusters at the cell surface are segregated from clusters of other cotransfected receptor tyrosine kinases. A mutational analysis, using coexpressed pairs of MuSK mutants and chimeras, demonstrates that the putative signal peptide is both necessary and sufficient for association with MuSK. Removal of the intracellular domain or most of the extracellular domain, or replacement of the transmembrane domain, does not abolish MuSK self-association. The N-terminus of the MuSK protein, however, is sufficient to recruit another receptor tyrosine kinase to MuSK clusters. Quantitation and statistical analysis of the amount of colocalization between coexpressed MuSK mutants and chimeras confirm these results.Genetic analyses for predictors of radiation response in glioblastoma
AbstractShih, H. A., Betensky, R. A., Dorfman, M. V., Louis, D. N., Loeffler, J. S., & Batchelor, T. T. (n.d.).Publication year
2005Journal title
International Journal of Radiation Oncology Biology PhysicsVolume
63Issue
3Page(s)
704-710AbstractPurpose: Radiotherapy (RT) for patients with glioblastoma improves survival and is recommended for nearly all patients with this diagnosis. However, the response to RT is variable in this patient population. Prior studies have suggested that underlying genetic alterations in the tumor may account for some of this treatment-related heterogeneity. It has been previously reported that epidermal growth factor receptor (EGFR) gene amplification and TP53 mutation correlate with the response to RT in patients with glioblastoma. Methods and Materials: We sought to identify molecular markers that could predict the response to RT, progression-free survival after RT, and overall survival among 75 glioblastoma patients treated with RT at a single institution. Genetic analyses assessed EGFR amplification, TP53 mutations, CDKN2A/p16 deletion, and losses of chromosomes 1p, 10q, and 19q. Results: Unlike previous reports, no association of EGFR amplification with response to RT, progression-free survival, or overall survival was found. Moreover, no association was found between these endpoints and the other genetic alterations assayed (TP53 mutation, CDKN2A/p16 deletion, loss of heterozygosity 1p, loss of heterozygosity 10q, and loss of heterozygosity 19q). However, in accordance with recent observations that the prognostic effects of genetic alterations in glioblastoma may depend on patient age, we observed age-dependent prognostic effects of TP53 and CDKN2A/p16 alterations in our patient population. For patients <57 years old, those harboring TP53 mutations had a decreased overall survival compared with patients without TP53 mutations. Similarly, deletion of CDKN2A/p16 in patients <57 years was associated with decreased progression-free survival after RT and a trend toward a shorter time to progression after RT compared with similar patients without the deletion. Conclusion: These data contrast with previous studies regarding the significant prognostic effect of EGFR with respect to RT response. Although our observations regarding the age-dependent prognostic effects of TP53 and CDKN2A/p16 are consistent with a prior report regarding these alterations, the present results should be considered preliminary, given the small sample size.Histology-based expression profiling yields novel prognostic markers in human glioblastoma
AbstractDong, S., Nutt, C. L., Betensky, R. A., Stemmer-Rachamimov, A. O., Denko, N. C., Ligon, K. L., Rowitch, D. H., & Louis, D. N. (n.d.).Publication year
2005Journal title
Journal of Neuropathology and Experimental NeurologyVolume
64Issue
11Page(s)
948-955AbstractAlthough the prognosis for patients with glioblastoma is poor, survival is variable, with some patients surviving longer than others. For this reason, there has been longstanding interest in the identification of prognostic markers for glioblastoma. We hypothesized that specific histologic features known to correlate with malignancy most likely express molecules that are directly related to the aggressive behavior of these tumors. We further hypothesized that such molecules could be used as biomarkers to predict behavior in a manner that might add prognostic power to sole histologic observation of the feature. We reasoned that perinecrotic tumor cell palisading, which denotes the most aggressive forms of malignant gliomas, would be a striking histologic feature on which to test this hypothesis. We therefore used laser capture microdissection and oligonucleotide arrays to detect molecules differentially expressed in perinecrotic palisades. A set of RNAs (including POFUT2, PTDSR, PLOD2, ATF5, and HK2) that were differentially expressed in 3 initially studied, microdissected glioblastomas also provided prognostic information in an independent set of 28 glioblastomas that did not all have perinecrotic palisades. On validation in a second, larger independent series, this approach could be applied to other human glioma types to derive tissue biomarkers that could offer ancillary prognostic and predictive information alongside standard histopathologic examination.In situ analysis of integrin and growth factor receptor signaling pathways in human glioblastomas suggests overlapping relationships with focal adhesion kinase activation
AbstractRiemenschneider, M. J., Mueller, W., Betensky, R. A., Mohapatra, G., & Louis, D. N. (n.d.).Publication year
2005Journal title
American Journal of PathologyVolume
167Issue
5Page(s)
1379-1387AbstractDeregulated integrin signaling is common in cancers, including glioblastoma. Integrin binding and growth factor receptor signaling activate focal adhesion kinase (FAK) and subsequently up-regulate extracellular regelated kinases (ERK-1/2), leading to cell-cycle progression and cell migration. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We examined these pathways primarily in situ using a panel of 30 glioblastomas and gene expression arrays, immunohistochemistry, and fluorescence in situ hybridization, emphasizing the histological distribution of molecular changes. Within individual tumors, increased expression of FAK, p-FAK, paxillin, ERK-1/2, and p-ERK-1/2 occurred in regions of elevated EGFK and/or PDGFRA expression. Moreover, FAK activation levels correlated with EGFR and PDGFRA expression, and p-FAK and EGFR expression co-localized at the single-cell level. In addition, integrin expression was enriched in EGFR/PDGFRA-overexpressing areas but was more regionally confined than FAK, p-FAK, and paxillin. Integrins β8 and α5β1 were most commonly expressed, often in a perinecrotic or perivascular pattern. Taken together, our data suggest that growth factor receptor overexpression facilitates alterations in the integrin signaling pathway. Thus, FAK may act in gliobiastoma as a downstream target of growth factor signaling, with integrals enhancing the impact of such signaling in the tumor microenvironment.Predicting in vitro fertilization live birth using stimulation day 6 estradiol, age, and follicle-stimulating hormone
AbstractSrouji, S. S., Mark, A., Levine, Z., Betensky, R. A., Hornstein, M. D., & Ginsburg, E. S. (n.d.).Publication year
2005Journal title
Fertility and SterilityVolume
84Issue
3Page(s)
795-797AbstractA retrospective analysis of IVF data was performed to determine predictors of live birth rate in four common stimulation protocols. A combination of day 6 E2 levels, age, and day 3 FSH levels can be used to predict cycle outcome.Risk factors for perineal wound complications following abdominoperineal resection
AbstractChristian, C. K., Kwaan, M. R., Betensky, R. A., Breen, E. M., Zinner, M. J., & Bleday, R. (n.d.).Publication year
2005Journal title
Diseases of the Colon and RectumVolume
48Issue
1Page(s)
43-48AbstractPURPOSE: Perineal wound complications are common following abdominoperineal resection. This study investigates the factors contributing to these complications. Methods: Patients undergoing abdominoperineal resection at our institution from June 1997 to May 2003 were reviewed. Significant predictors associated with minor (separation <2 cm, stitch abscesses, or sinus tracts) or major (>2 cm of separation, reoperation required, or readmission) wound complications were ascertained. Results: Of 153 patients, there were 22 major (14 percent) and 32 minor (24 percent) wound complications. Patients with anal cancer had a higher rate of major complications than those with rectal cancer or inflammatory bowel disease. Minor wound complications were more common in patients with anal cancer and inflammatory bowel disease than those with rectal cancer. Factors associated with a higher rate of major wound complications included flap closure, tumor size, body mass index, diabetes, and indication for the procedure. When the subset of patients with rectal cancer was considered, higher rates of major wounds were associated with increased body mass index, diabetes, and stage. Minor complications were associated with a two-team approach and increasing body mass index. Conclusions: This is currently the largest review of perineal wound complications following abdominoperineal resection. Patients with anal cancer and inflammatory bowel disease were at higher risk for perineal wound complications than those with rectal cancer. Preoperative radiation and primary closure were not associated with increased complications following abdominoperineal resection for rectal cancer.Somatic mitochondrial DNA mutations in single neurons and glia
AbstractCantuti-Castelvetri, I., Lin, M. T., Zheng, K., Keller-McGandy, C. E., Betensky, R. A., Johns, D. R., Beal, M. F., Standaert, D. G., & Simon, D. K. (n.d.).Publication year
2005Journal title
Neurobiology of AgingVolume
26Issue
10Page(s)
1343-1355AbstractSomatic mitochondrial DNA (mtDNA) point mutations reach high levels in the brain. However, the cell types that accumulate mutations and the patterns of mutations within individual cells are not known. We have quantified somatic mtDNA mutations in 28 single neurons and in 18 single glia from post-mortem human substantia nigra of six control subjects. Both neurons and glia contain mtDNA with somatic mutations. Single neurons harbor a geometric mean (95% CI) of 200.3 (152.9-262.4) somatic mtDNA point mutations per million base pairs, compared to 133.8 (97.5-184.9) for single glia (p = 0.0251). If mutations detected multiple times in the same cell are counted only once, the mean mutation level per million base pairs remains elevated in single neurons (146.9; 124.0-174.2) compared to single glia (100.5; 81.5-126.5; p = 0.009). Multiple distinct somatic point mutations are present in different cells from the same subject. Most of these mutations are individually present at low levels (less than 10-20% of mtDNA molecules), but with high aggregate mutation levels, particularly in neurons. These mutations may contribute to changes in brain function during normal aging and neurodegenerative disorders.