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
Estimating Time to Disease Progression Comparing Transition Models and Survival Methods-An Analysis of Multiple Sclerosis Data
AbstractMandel, M., Mercier, F., Eckert, B., Chin, P., & Betensky, R. (n.d.).Publication year
2013Journal title
BiometricsVolume
69Issue
1Page(s)
225-234AbstractThis article reports an analysis that aims to quantify the effect of fingolimod, an oral treatment for relapsing remitting multiple sclerosis (MS), on disability progression. The standard approach utilizes survival analysis methods, which may be problematic for MS studies that assess disability at only a few time points and include as a cardinal feature both relapses and remissions. Instead, a Markov transition model, originally developed in the framework of longitudinal data, is fit, and its special probabilistic properties are used to estimate survival curves for time to disability progression. The transition approach models the whole disability process and uses all available transition data for inference, while survival methods concentrate on a single event of interest and use only time to event data. This article compares the transition model approach to survival analysis methods, and discusses the differences in the interpretations of the estimated parameters. It applies both models to data obtained from two phase 3 clinical trials and finds that both yield positive effects for the new treatment compared to placebo, and provide similar estimates for the probability of disability progression over time. The transition model enables calculation of covariate-specific transition matrices that describe the short-term effect of treatment and other covariates on the disability process.Estimating time to event from longitudinal categorical data : An analysis of multiple sclerosis progression
AbstractMandel, M., Gauthier, S. A., Guttmann, C. R., Weiner, H. L., & Betensky, R. (n.d.).Publication year
2007Journal title
Journal of the American Statistical AssociationVolume
102Issue
480Page(s)
1254-1266AbstractThe expanded disability status scale (EDSS) is an ordinal score that measures progression in multiple sclerosis (MS). Progression is defined as reaching EDSS of a certain level (absolute progression) or increasing EDSS by one point (relative progression). Survival methods for time to progression are not adequate for such data because they do not exploit the EDSS level at the end of follow-up. Instead, we suggest a Markov transitional model applicable for repeated categorical or ordinal data. This approach enables derivation of covariate-specific survival curves, obtained after estimation of the regression coefficients and manipulations of the resulting transition matrix. Large-sample theory and resampling methods are employed to derive pointwise confidence intervals, which perform well in simulation. Methods for generating survival curves for time to EDSS of a certain level, time to increase EDSS by at least one point, and time to two consecutive visits with EDSS greater than 3 are described explicitly. The regression models described are easily implemented using standard software packages. Survival curves are obtained from the regression results using packages that support simple matrix calculation. We present and demonstrate our method on data collected at the Partners Multiple Sclerosis Center in Boston. We apply our approach to progression defined by time to two consecutive visits with EDSS greater than 3 and calculate crude (without covariates) and covariate-specific curves.Estimating time-to-event from longitudinal ordinal data using random-effects Markov models : Application to multiple sclerosis progression
AbstractMandel, M., & Betensky, R. (n.d.).Publication year
2008Journal title
BiostatisticsVolume
9Issue
4Page(s)
750-764AbstractLongitudinal ordinal data are common in many scientific studies, including those of multiple sclerosis (MS), and are frequently modeled using Markov dependency. Several authors have proposed random-effects Markov models to account for heterogeneity in the population. In this paper, we go one step further and study prediction based on random-effects Markov models. In particular, we show how to calculate the probabilities of future events and confidence intervals for those probabilities, given observed data on the ordinal outcome and a set of covariates, and how to update them over time. We discuss the usefulness of depicting these probabilities for visualization and interpretation of model results and illustrate our method using data from a phase III clinical trial that evaluated the utility of interferon beta-1a (trademark Avonex) to MS patients of type relapsing-remitting.Estimation and regression for partially truncated data
AbstractBetensky, R., & Qian, J. (n.d.).Publication year
2024Journal title
Journal of Nonparametric StatisticsAbstractJournal of Nonparametric StatisticsEstimation of the censoring distribution in clinical trials
AbstractJiang, S., Swanson, D., & Betensky, R. (n.d.).Publication year
2021Journal title
Contemporary Clinical Trials CommunicationsVolume
23AbstractClinical studies with time to event endpoints typically report the median follow-up (i.e., censoring) time for the subjects in the trial, alongside the median time to event. The reason for this is to provide information about the opportunity for subjects in the study to experience the event of interest (Betensky, 2015 [1]). The median follow-up time is often calculated from the Kaplan–Meier estimate for time to censoring. In most clinical studies, the censoring time is a composite measure, defined as the minimum of time to drop-out from the study and time to administrative end of study. The time to drop-out component may or may not be observed; it is observed only if drop-out occurs before the event and the end of the study. However, the time to end of study is observed for each subject, as it is the time from entry to the study to the calendar date that is administratively set as the end of the study. It is known even for subjects who have the event prior to the end of the study. This decomposition of the censoring time into a time that is itself potentially censored and a time that is fully observed raises the interesting question of whether estimation of the censoring distribution could be improved through a decoupling of these times. We demonstrate in simulations that consideration of censoring in this way yields reduced variability under some circumstances and should be used in practice. We illustrate these concepts through application to a meningioma study.Estimation of the censoring distribution in clinical trials
AbstractBetensky, R., Jiang, S., Swanson, D., & Betensky, R. A. (n.d.).Publication year
2021Journal title
Contemporary clinical trials communicationsVolume
23Page(s)
100842AbstractClinical studies with time to event endpoints typically report the median follow-up (i.e., censoring) time for the subjects in the trial, alongside the median time to event. The reason for this is to provide information about the opportunity for subjects in the study to experience the event of interest (Betensky, 2015 [1]). The median follow-up time is often calculated from the Kaplan-Meier estimate for time to censoring. In most clinical studies, the censoring time is a composite measure, defined as the minimum of time to drop-out from the study and time to administrative end of study. The time to drop-out component may or may not be observed; it is observed only if drop-out occurs before the event and the end of the study. However, the time to end of study is observed for each subject, as it is the time from entry to the study to the calendar date that is administratively set as the end of the study. It is known even for subjects who have the event prior to the end of the study. This decomposition of the censoring time into a time that is itself potentially censored and a time that is fully observed raises the interesting question of whether estimation of the censoring distribution could be improved through a decoupling of these times. We demonstrate in simulations that consideration of censoring in this way yields reduced variability under some circumstances and should be used in practice. We illustrate these concepts through application to a meningioma study.Evidence-based decision support for neurological diagnosis reduces errors and unnecessary workup
AbstractSegal, M. M., Williams, M. S., Gropman, A. L., Torres, A. R., Forsyth, R., Connolly, A. M., El-Hattab, A. W., Perlman, S. J., Samanta, D., Parikh, S., Pavlakis, S. G., Feldman, L. K., Betensky, R., & Gospe, S. M. (n.d.).Publication year
2014Journal title
Journal of Child NeurologyVolume
29Issue
4Page(s)
487-492AbstractUsing vignettes of real cases and the SimulConsult diagnostic decision support software, neurologists listed a differential diagnosis and workup before and after using the decision support. Using the software, there was a significant reduction in error, up to 75% for diagnosis and 56% for workup. This error reduction occurred despite the baseline being one in which testers were allowed to use narrative resources and Web searching. A key factor that improved performance was taking enough time (>2 minutes) to enter clinical findings into the software accurately. Under these conditions and for instances in which the diagnoses changed based on using the software, diagnostic accuracy improved in 96% of instances. There was a 6% decrease in the number of workup items accompanied by a 34% increase in relevance. The authors conclude that decision support for a neurological diagnosis can reduce errors and save on unnecessary testing.Examination of the clinicopathologic continuum of Alzheimer disease in the autopsy cohort of the national alzheimer coordinating center
AbstractSerrano-Pozo, A., Qian, J., Monsell, S. E., Frosch, M. P., Betensky, R., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Journal of Neuropathology and Experimental NeurologyVolume
72Issue
12Page(s)
1182-1192AbstractTo test the hypothesis that Alzheimer disease (AD) is a clinical and pathologic continuum between normal aging and end-stage dementia, we selected a convenience sample of subjects from the National Alzheimer Coordinating Center 2005 to 2012 autopsy cohort (n = 2,083) with the last clinical evaluation within 2 years before autopsy and no other primary neuropathologic diagnosis. Demographic and neuropathologic characteristics were correlated with the Clinical Dementia Rating-Sum of Boxes in the 835 subjects meeting these criteria. Both neuritic plaques and neurofibrillary tangles independently predicted Clinical Dementia Rating-Sum of Boxes. Severe small-vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also independently associated with the degree of cognitive impairment. By contrast, education was a strong independent protective factor against cognitive deficits. The cause of mild to moderate dementia remained uncertain in 14% of the patients. Inverse probability weighting suggests the generalizability of these results to nonautopsied cohorts. These data indicate that plaques and tangles independently contribute to cognitive impairment, that concurrent vascular disease strongly correlates with cognitive dysfunction even in a sample selected to represent the AD pathologic continuum, and that education further modifies clinical expression. Thus, multiple concomitant etiologies of brain damage and premorbid characteristics contribute to the uncertainty of AD clinicopathologic correlations based only on tangles and plaques.Exchanging Dermatoscopes for Stethoscopes : Has the COVID-19 Pandemic Highlighted Gaps in US Dermatology Residency Training?
AbstractShaw, K. S., Karagounis, T. K., Yin, L., Svigos, K., Gibbon, G. T., Betensky, R., & Lo Sicco, K. I. (n.d.).Publication year
2020Journal title
Journal of Drugs in DermatologyVolume
19Issue
9Page(s)
905-906Abstract~Exploring predictors of response to dacomitinib in EGFR-amplified recurrent glioblastoma
AbstractChi, A. S., Cahill, D. P., Reardon, D. A., Wen, P. Y., Mikkelsen, T., Peereboom, D. M., Wong, E. T., Gerstner, E. R., Dietrich, J., Plotkin, S. R., Norden, A. D., Lee, E. Q., Nayak, L., Tanaka, S., Wakimoto, H., Lelic, N., Koerner, M. V., Klofas, L. K., Bertalan, M. S., … Batchelor, T. T. (n.d.).Publication year
2019Journal title
JCO Precision OncologyVolume
4Page(s)
593-604AbstractPURPOSE Despite the high frequency of EGFR genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for EGFR gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial. PATIENTS AND METHODS We retrospectively explored whether previously described EGFR extracellular domain (ECD)–sensitizing mutations in the context of EGFR gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration. RESULTS We found that dacomitinib effectively penetrates contrast-enhancing GBM tumors. Among all 56 treated patients, 8 (14.3%) had a clinical benefit as defined by a duration of treatment of at least 6 months, of whom 5 (8.9%) remained progression free for at least 1 year. Presence of EGFRvIII or EGFR ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression. CONCLUSION While dacomitinib was not effective in most patients with EGFR-amplified GBM, a subset experienced a durable, clinically meaningful benefit. Moreover, EGFRvIII and EGFR ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.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., 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.Fallopian tube correlates of ovarian serous borderline tumors
AbstractBetensky, R., Laury, A. R., Ning, G., Quick, C. M., Bijron, J., Parast, M. M., Betensky, R. A., Vargas, S. O., McKeon, F. D., Xian, W., Nucci, M. R., & Crum, C. P. (n.d.).Publication year
2011Journal title
American Journal of Surgical PathologyVolume
35Issue
12Page(s)
1759-1765AbstractOvarian serous borderline tumors (SBTs) are presumed to originate in the ovarian cortex or peritoneal surface. The pathogenetic role of the fallopian tube (FT) is unclear; however, recently, secretory cell outgrowths (SCOUTs) lacking PAX2 expression were described in benign FTs. This study addressed (1) the differentiation characteristics of SBTs and (2) the frequency of SCOUTs lacking PAX2 expression in the FTs of patients with SBTs and compared (3) SCOUT morphology and (4) PAX2 expression with SBTs. SBTs and FT epithelium shared both ciliated (p73) and secretory (HMFG2) differentiation. PAX2-null SCOUT frequency in FT cross-sections from patients with SBTs was 0.28 (110 of 398) versus 0.112 in benign hysterectomies and nearly 0 in pediatric and postpartum sterilization specimens (P=Family History of Diabetes Is a Major Determinant of Endothelial Function
AbstractGoldfine, A. B., Beckman, J. A., Betensky, R., 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. (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.Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline
AbstractHanseeuw, B. J., Betensky, R., Schultz, A. P., Papp, K. V., Mormino, E. C., Sepulcre, J., Bark, J. S., Cosio, D. M., LaPoint, M., Chhatwal, J. P., Rentz, D. M., Sperling, R. A., & Johnson, K. A. (n.d.).Publication year
2017Journal title
Annals of NeurologyVolume
81Issue
4Page(s)
583-596AbstractObjective: The aim of this article was to evaluate in normal older adults and preclinical Alzheimer's disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline. Methods: We acquired positron emission tomography using F18 flortaucipir (tau), C11 Pittsburgh compound B (amyloid), and F18 fluorodeoxyglucose (FDG) in 90 clinically normal elderly of the Harvard Aging Brain Study. Results: Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly. In contrast, frontal hypometabolism related to the common age-related entorhinal tauopathy, but this dysfunction was independent of amyloid, and did not predict significant memory decline. Neocortical tauopathy was positively associated with metabolism in individuals with subthreshold amyloid, suggesting that glucose metabolism increases before decreasing in the course of preclinical AD. Interpretation: Our study identified a synergistic effect of amyloid and tau deposits and demonstrated, for the first time, in normal elderly its link to AD-like hypometabolism and to AD-like memory decline. The amyloid effect was observed with tau in neocortex, but not with tau in entorhinal cortex, which is the common site of age-related tauopathy. Entorhinal tau was associated with frontal hypometabolism, but this dysfunction was not associated with memory loss. Ann Neurol 2017;81:583–596.Following the Dropouts - Interpreting an 11-Year Follow-up Study
AbstractBetensky, R., & Betensky, R. A. (n.d.).Publication year
2023Journal title
NEJM evidenceVolume
2Issue
8Page(s)
EVIDe2300137AbstractIn this edition of , Lohmander et al. report on the 11-year follow-up for a randomized clinical trial (KANON [Knee Anterior Cruciate Ligament Nonsurgical vs. Surgical Treatment]) of early anterior cruciate ligament reconstruction (ACLR) versus optional delayed ACLR in young, active adults. This is the third publication reporting on this trial, which enrolled 121 participants from February 2002 through June 2006. A 2010 article reported on the 2-year follow-up, and a 2013 article reported on the 5-year follow-up. Both of these analyses concluded that early ACLR did not lead to improved patient-reported outcomes relative to optional delayed ACLR.Gain of chromosome arm 1q in atypical meningioma correlates with shorter progression-free survival
AbstractBetensky, R., Jansen, M., Mohapatra, G., Betensky, R. A., Keohane, C., & Louis, D. N. (n.d.).Publication year
2012Journal title
Neuropathology and Applied NeurobiologyVolume
38Issue
2Page(s)
213-219AbstractAims: Atypical (World Health Organization grade II) meningiomas have moderately high recurrence rates; even for completely resected tumours, approximately one-third will recur. Post-operative radiotherapy may aid local control and improve survival, but carries the risk of side effects. More accurate prediction of recurrence risk is therefore needed for patients with atypical meningioma. Previously, we used high-resolution array comparative genomic hybridization to identify genetic variations in 47 primary atypical meningiomas and found that approximately 60% of tumours show gain of 1q at 1q25.1 and 1q25.3 to 1q32.1 and that 1q gain appeared to correlate with shorter progression-free survival. This study aimed to validate and extend these findings in an independent sample. Methods: Eighty-six completely resected atypical meningiomas (with 25 recurrences) from two neurosurgical centres in Ireland were identified and clinical follow-up was obtained. Utilizing a dual-colour interphase fluorescence in situ hybridization assay, 1q gain was assessed using Bacterial Artificial Chromosome probes directed against 1q25.1 and 1q32.1. Results: The results confirm the high prevalence of 1q gain at these loci in atypical meningiomas. We further show that gain at 1q32.1 and age each correlate with progression-free survival in patients who have undergone complete surgical resection of atypical meningiomas. Conclusions: These independent findings suggest that assessment of 1q copy number status can add clinically useful information for the management of patients with atypical meningiomas.Gene expression-based classification of malignant gliomas correlates better with survival than histological classification
AbstractNutt, C. L., Mani, D. R., Betensky, R., Tamayo, P., Cairncross, J. G., Ladd, C., Pohl, U., Hartmann, C., McLaughlin, M. E., Batchelor, T. T., Black, P. M., Von Deimling, A., Pomeroy, S. L., Golub, T. R., & Louis, D. N. (n.d.).Publication year
2003Journal title
Cancer ResearchVolume
63Issue
7Page(s)
1602-1607AbstractIn modern clinical neuro-oncology, histopathological diagnosis affects therapeutic decisions and prognostic estimation more than any other variable. Among high-grade gliomas, histologically classic glioblastomas and anaplastic oligodendrogliomas follow markedly different clinical courses. Unfortunately, many malignant gliomas are diagnostically challenging; these nonclassic lesions are difficult to classify by histological features, generating considerable interobserver variability and limited diagnostic reproducibility. The resulting tentative pathological diagnoses create significant clinical confusion. We investigated whether gene expression profiling, coupled with class prediction methodology, could be used to classify high-grade gliomas in a manner more objective, explicit, and consistent than standard pathology. Microarray analysis was used to determine the expression of ∼12,000 genes in a set of 50 gliomas, 28 glioblastomas and 22 anaplastic oligodendrogliomas. Supervised learning approaches were used to build a two-class prediction model based on a subset of 14 glioblastomas and 7 anaplastic oligodendrogliomas with classic histology. A 20-feature κ-nearest neighbor model correctly classified 18 of the 21 classic cases in leave-one-out cross-validation when compared with pathological diagnoses. This model was then used to predict the classification of clinically common, histologically nonclassic samples. When tumors were classified according to pathology, the survival of patients with nonclassic glioblastoma and nonclassic anaplastic oligodendroglioma was not significantly different (P = 0.19). However, class distinctions according to the model were significantly associated with survival outcome (P = 0.05). This class prediction model was capable of classifying high-grade, nonclassic glial tumors objectively and reproducibly. Moreover, the model provided a more accurate predictor of prognosis in these nonclassic lesions than did pathological classification. These data suggest that class prediction models, based on defined molecular profiles, classify diagnostically challenging malignant gliomas in a manner that better correlates with clinical outcome than does standard pathology.Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain
AbstractHudry, E., Dashkoff, J., Roe, A. D., Takeda, S., Koffie, R. M., Hashimoto, T., Scheel, M., Spires-Jones, T., Arbel-Ornath, M., Betensky, R., Davidson, B. L., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Science Translational MedicineVolume
5Issue
212AbstractInheritance of the ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor associated with the sporadic form of Alzheimer's disease (AD), whereas the rare APOE ε2 allele has the opposite effect. However, the mechanisms whereby APOE confers risk and protection remain uncertain. We used a gene transfer approach to bathe the cortex of amyloid plaque-bearing transgenic mice with virally expressed human APOE. We monitored amyloid-β (Aβ) with multiphoton imaging, in vivo microdialysis, and postmortem array tomography to study the kinetics of human APOE mediated changes in Aβ-related neurotoxicity in a mouse model of AD. We observed that human APOE4 increased the concentrations of oligomeric Aβ within the interstitial fluid and exacerbated plaque deposition; the converse occurred after exposure to human APOE2. Peri-plaque synapse loss and dystrophic neurites were also worsened by APOE4 or attenuated by APOE2. Egress of Aβ from the central nervous system (CNS) into the plasma was diminished by APOE3 and APOE4 compared to APOE2, in accord with isoform-specific retention of Aβ in the CNS. Overall, our data show a differential effect of human APOE isoforms on amyloid deposition and clearance in transgenic mice and, more importantly, on Aβ-mediated synaptotoxicity. These results suggest that the APOE genetic risk is mediated by Aβ, and that therapeutic approaches aimed at decreasing APOE4, or increasing APOE2, may be beneficial in AD.Genetic analyses for predictors of radiation response in glioblastoma
AbstractShih, H. A., Betensky, R., 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 patientsGenetic determinants of hearing loss associated with vestibular schwannomas
AbstractStankovic, K. M., Mrugala, M. M., Martuza, R. L., Silver, M., Betensky, R., Nadol, J. B., & Stemmer-Rachamimov, A. O. (n.d.).Publication year
2009Journal title
Otology and NeurotologyVolume
30Issue
5Page(s)
661-667AbstractHYPOTHESIS: The severity of hearing loss (HL) associated with vestibular schwannomas (VSs) is influenced by genes expressed by the VSs. BACKGROUND: Hearing loss is the most common presenting symptoms in patients with VSs, yet its pathophysiology remains elusive. Previous studies have suggested that VSs cause HL not only by inducing degeneration of the auditory nerve by compression but also by promoting degeneration of the inner ear. This study aimed to determine whether there is a molecular basis for differences in HL associated with VSs. METHODS: Surgical specimens of VSs were collected from 13 patients and were divided into a group associated with good (word recognition >70% and pure-tone average ≤30 dB) or poor hearing. Whole-genome expression profiling of VSs was performed with the Affymetrix GeneChip Human X3P Array. The expression of select genes was validated using real-time quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. Because of a small sample size, exact nonparametric tests were used to assess the association between good versus poor hearing and specific histological features of the tumors and patient demographics. RESULTS: Using gene set enrichment analysis, the chromosomal region 3q27 was found to be significantly different between the 2 groups of tumors. This region includes peroxisomal biogenesis factor 5-like gene, which was underexpressed in VSs with poor hearing. The expression of 3 other genes from different chromosomes was significantly different between the 2 groups: RAD54B, prostate-specific membrane antigen-like, and carcinoembryonic antigen. CONCLUSION: This study identified several molecular alterations in VSs stratified by hearing. These alterations may determine the severity of HL associated with VSs and may represent potential therapeutic targets to prevent or reduce HL in theses patients.Genetic overlap between vascular pathologies and Alzheimer's dementia and potential causal mechanisms
AbstractLin, Y. F., Smith, A. V., Aspelund, T., Betensky, R., Smoller, J. W., Gudnason, V., Launer, L. J., & Blacker, D. (n.d.).Publication year
2019Journal title
Alzheimer's and DementiaVolume
15Issue
1Page(s)
65-75AbstractIntroduction: We sought to examine the genetic overlap between vascular pathologies and Alzheimer's disease (AD) dementia, and the potential mediating role of vascular pathologies between AD-related genetic variants and late-life cognition. Methods: For 2907 stroke-free older individuals, we examined the association of polygenic risk scores for AD dementia (ADPRSs) with vascular pathologies and with cognition. Mediation analyses addressed whether association between ADPRSs and cognition was mediated by a vascular pathology. Results: ADPRSs were associated with lobar cerebral microbleeds, white matter lesion load, and coronary artery calcification, mostly explained by single nucleotide polymorphisms in the 19q13 region. The effect of ADPRSs on cognition was partially but significantly mediated by cerebral microbleeds, white matter lesions, and coronary artery calcification. Discussion: Our findings provide evidence for genetic overlap, mostly due to apolipoprotein E (APOE) gene, between vascular pathologies and AD dementia. The association between AD polygenic risk and late-life cognition is mediated in part via effects on vascular pathologies.Genetic risk factors in Parkinson's disease : Single gene effects and interactions of genotypes
AbstractGöbel, A., Macklin, E. A., Winkler, S., Betensky, R., Klein, C., Lohmann, K., & Simon, D. K. (n.d.).Publication year
2012Journal title
Journal of NeurologyVolume
259Issue
11Page(s)
2503-2505Abstract~Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization : Facilitating analysis of archival gliomas
AbstractMohapatra, G., Engler, D. A., Starbuck, K. D., Kim, J. C., Bernay, D. C., Scangas, G. A., Rousseau, A., Batchelor, T. T., Betensky, R., & Louis, D. N. (n.d.).Publication year
2011Journal title
Acta NeuropathologicaVolume
121Issue
4Page(s)
529-543AbstractArray comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA). Because diffuse malignant gliomas are often sampled by small biopsies, formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis; FFPE tissues are also needed to study the intratumoral heterogeneity that characterizes these neoplasms. In this paper, we present a combination of evaluations and technical advances that provide strong support for the ready use of oligonucleotide aCGH on FFPE diffuse gliomas. We first compared aCGH using bacterial artificial chromosome (BAC) arrays in 45 paired frozen and FFPE gliomas, and demonstrate a high concordance rate between FFPE and frozen DNA in an individual clone-level analysis of sensitivity and specificity, assuring that under certain array conditions, frozen and FFPE DNA can perform nearly identically. However, because oligonucleotide arrays offer advantages to BAC arrays in genomic coverage and practical availability, we next developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. To demonstrate utility in FFPE tissues, we applied this approach to biphasic anaplastic oligoastrocytomas and demonstrate CNA differences between DNA obtained from the two components. Therefore, BAC and oligonucleotide aCGH can be sensitive and specific tools for detecting CNAs in FFPE DNA, and novel labeling techniques enable the routine use of oligonucleotide arrays for FFPE DNA. In combination, these advances should facilitate genome-wide analysis of rare, small and/or histologically heterogeneous gliomas from FFPE tissues.Genomic and Transcriptomic Analyses of NF1-Mutant Melanoma Identify Potential Targeted Approach for Treatment
AbstractBetensky, R., Jour, G., Illa-Bochaca, I., Ibrahim, M., Donnelly, D., Zhu, K., Miera, E. V., Vasudevaraja, V., Mezzano, V., Ramswami, S., Yeh, Y.- H., Winskill, C., Betensky, R. A., Mehnert, J., & Osman, I. (n.d.).Publication year
2023Journal title
The Journal of investigative dermatologyVolume
143Issue
3Page(s)
444-455.e8AbstractThere is currently no targeted therapy to treat NF1-mutant melanomas. In this study, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1 wild-type melanoma to reveal potential treatment targets for this subset of patients. Genomic alterations were verified using qPCR, and differentially expressed genes were independently validated using The Cancer Genome Atlas data and immunohistochemistry. Digital spatial profiling with multiplex immunohistochemistry and immunofluorescence were used to validate the signatures. The efficacy of combinational regimens driven by these signatures was tested through in vitro assays using low-passage cell lines. Pathogenic NF1 mutations were identified in 27% of cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 than NF1 wild-type (P = 0.008), which was independently validated both in The Cancer Genome Atlas dataset (P = 0.01, P = 0.03) and with immunohistochemistry (P = 0.013, P = 0.036), respectively. Digital spatial profiling analysis showed upregulation of LY6E within the tumor cells (false discovery rate < 0.01, log2 fold change > 1), confirmed with multiplex immunofluorescence showing colocalization of LY6E in melanoma cells. The combination of MAPK/extracellular signal‒regulated kinase kinase and CDC20 coinhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-mutant cell lines. In conclusion, NF1-mutant melanoma is associated with a distinct genomic and transcriptomic profile. Our data support investigating CDC20 inhibition with MAPK pathway inhibitors as a targeted regimen in this melanoma subtype.