Rebecca A Betensky

Chair of the Department of Biostatistics

Professor of Biostatistics

Professional overview

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.

Education

AB, Mathematics, Harvard University, Cambridge, MA

PhD, Statistics, Stanford University, Stanford, CA

Areas of research and study

Biology

Biostatistics

Neuroepidemiology

Neurology

Neurostatistics

Translational science

Publications

Publications

Calcineurin inhibition with systemic FK506 treatment increases dendritic branching and dendritic spine density in healthy adult mouse brain

Spires-Jones, T. L., Kay, K., Matsouka, R., Rozkalne, A., Betensky, R., & Hyman, B. T. (n.d.).

Publication year

2011

Journal title

Neuroscience letters

Volume

487

Issue

3

Page(s)

260-263

10.1016/j.neulet.2010.10.033

Abstract

Abstract

Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and recent data suggest that calcineurin activation mediates some of the neurotoxicity of the Alzheimer related neurotoxin Aβ. Immunosuppression via calcineurin inhibition with the compound FK506 is an important treatment for organ transplant patients. Here we use Golgi impregnation techniques, along with a new survival analysis-based statistical approach for analysis of dendritic complexity, to show that in healthy adult mice one week of treatment with FK506 affects both the branching patterns and dendritic spine density of cortical neurons. These results indicate that calcineurin inhibition leads to readily detectable changes in brain morphology, further implicating calcineurin related pathways in both the function and structure of the adult brain.

Comparison of clinical subgroup aCGH profiles through pseudolikelihood ratio tests

Engler, D., Shen, Y., Gusella, J., & Betensky, R. (n.d.).

Publication year

2011

Journal title

Statistical Applications in Genetics and Molecular Biology

Volume

10

Issue

1

10.2202/1544-6115.1407

Abstract

Abstract

Array-based Comparative Genomic Hybridization (aCGH) is a microarray-based technology that assists in identification of DNA sequence copy number changes across the genome. Examination of differences in instability phenotype, or pattern of copy number alterations, between cancer subtypes can aid in classification of cancers and lead to better understanding of the underlying cytogenic mechanism. Instability phenotypes are composed of a variety of copy number alteration features including height or magnitude of copy number alteration level, frequency of transition between copy number states such as gain and loss, and total number of altered clones or probes. That is, instability phenotype is multivariate in nature. Current methods of instability phenotype assessment, however, are limited to univariate measures and are therefore limited in both sensitivity and interpretability. In this paper, a novel method of instability assessment is presented that is based on the Engler et al. (2006) pseudolikelhood approach for aCGH data analysis. Through use of a pseudolikelihood ratio test (PLRT), more sensitive assessment of instability phenotype differences between cancer subtypes is possible. Evaluation of the PLRT method is conducted through analysis of a meningioma data set and through simulation studies. Results are shown to be more accurate and more easily interpretable than current measures of instability assessment.

Diagnosis of hydatidiform moles by polymorphic deletion probe fluorescence in Situ hybridization

Chiang, S., Fazlollahi, L., Nguyen, A., Betensky, R., Roberts, D. J., & Iafrate, A. J. (n.d.).

Publication year

2011

Journal title

Journal of Molecular Diagnostics

Volume

13

Issue

4

Page(s)

406-415

10.1016/j.jmoldx.2011.02.002

Abstract

Abstract

Because products of conception often contain maternal and villous tissues, the determination of maternal and villous genotypes based on genetic polymorphisms can help discern maternal and paternal chromosomal contribution and aid in the diagnosis of hydatidiform moles. Polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes based on copy number variants are highly polymorphic and allow in situ determination of genetic identity. By using three informative PDPs on chromosomes 2p, 4q, and 8p, we compared maternal with villous genotypes and determined the ploidy of villous tissue. PDP FISH was performed on 13 complete moles, 13 partial moles, 13 nonmolar abortions, and an equivocal hydropic abortion. PDP FISH permitted definitive diagnosis of complete moles in five of 13 cases for which maternal and villous genotypes were mutually exclusive. A complete mole was highly suspected when all three PDP loci showed homozygous villous genotypes. The diagnosis of a complete mole by PDP FISH yielded a theoretical test sensitivity of 87.5%, specificity of 91.8%, an observed test sensitivity of 100%, and specificity of 92.3%. Triploidy was observed in all partial moles, in which diandric triploidy was confirmed in six cases. In the equivocal hydropic abortion, PDP FISH combined with p57 immunofluorescence revealed placental androgenetic/biparental mosaicism. PDP FISH can be used in clinical practice and research studies to subclassify hydatidiform moles and evaluate unusual products of conception.

Fallopian tube correlates of ovarian serous borderline tumors

Betensky, 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

2011

Journal title

American Journal of Surgical Pathology

Volume

35

Issue

12

Page(s)

1759-1765

10.1097/PAS.0b013e318233b0f7

Abstract

Abstract

Ovarian 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=

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

Mohapatra, 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

2011

Journal title

Acta Neuropathologica

Volume

121

Issue

4

Page(s)

529-543

10.1007/s00401-010-0773-z

Abstract

Abstract

Array 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.

Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma

Snuderl, M., Fazlollahi, L., Le, L. P., Nitta, M., Zhelyazkova, B. H., Davidson, C. J., Akhavanfard, S., Cahill, D. P., Aldape, K. D., Betensky, R., Louis, D. N., & Iafrate, A. J. (n.d.).

Publication year

2011

Journal title

Cancer Cell

Volume

20

Issue

6

Page(s)

810-817

10.1016/j.ccr.2011.11.005

Abstract

Abstract

Tumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies.

Primary CNS lymphoma in children and adolescents : A descriptive analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG)

Abla, O., Weitzman, S., Blay, J. Y., O'Neill, B. P., Abrey, L. E., Neuwelt, E., Doolittle, N. D., Baehring, J., Pradhan, K., Martin, S. E., Guerrera, M., Shah, S., Ghesquieres, H., Silver, M., Betensky, R., & Batchelor, T. (n.d.).

Publication year

2011

Journal title

Clinical Cancer Research

Volume

17

Issue

2

Page(s)

346-352

10.1158/1078-0432.CCR-10-1161

Abstract

Abstract

Purpose: To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL). Experimental Design: A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries. Results: Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively. Conclusion: This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival.

Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease

Serrano-Pozo, A., Mielke, M. L., Gómez-Isla, T., Betensky, R., Growdon, J. H., Frosch, M. P., & Hyman, B. T. (n.d.).

Publication year

2011

Journal title

American Journal of Pathology

Volume

179

Issue

3

Page(s)

1373-1384

10.1016/j.ajpath.2011.05.047

Abstract

Abstract

Senile plaques are a prominent pathological feature of Alzheimer's disease (AD), but little is understood about the association of glial cells with plaques or about the dynamics of glial responses through the disease course. We investigated the progression of reactive glial cells and their relationship with AD pathological hallmarks to test whether glial cells are linked only to amyloid deposits or also to tangle deposition, thus integrating both lesions as a marker of disease severity. We conducted a quantitative stereology-based post-mortem study on the temporal neocortex of 15 control subjects without dementia and 91 patients with AD, including measures of amyloid load, neurofibrillary tangles, reactive astrocytes, and activated microglia. We also addressed the progression of glial responses in the vicinity (≤50 μm) of dense-core plaques and tangles. Although the amyloid load reached a plateau early after symptom onset, astrocytosis and microgliosis increased linearly throughout the disease course. Moreover, glial responses correlated positively with tangle burden, whereas astrocytosis correlated negatively with cortical thickness. However, neither correlated with amyloid load. Glial responses increased linearly around existing plaques and in the vicinity of tangles. These results indicate that the progression of astrocytosis and microgliosis diverges from that of amyloid deposition, arguing against a straightforward relationship between glial cells and plaques. They also suggest that reactive glia might contribute to the ongoing neurodegeneration.

Assessing Population Level Genetic Instability via Moving Average

McDaniel, S., Minnier, J., Betensky, R., Mohapatra, G., Shen, Y., Gusella, J. F., Louis, D. N., & Cai, T. (n.d.).

Publication year

2010

Journal title

Statistics in Biosciences

Volume

2

Issue

2

Page(s)

120-136

10.1007/s12561-010-9028-8

Abstract

Abstract

Tumoral tissues tend to generally exhibit aberrations in DNA copy number that are associated with the development and progression of cancer. Genotyping methods such as array-based comparative genomic hybridization (aCGH) provide means to identify copy number variation across the entire genome. To address some of the shortfalls of existing methods of DNA copy number data analysis, including strong model assumptions, lack of accounting for sampling variability of estimators, and the assumption that clones are independent, we propose a simple graphical approach to assess population-level genetic alterations over the entire genome based on moving average. Furthermore, existing methods primarily focus on segmentation and do not examine the association of covariates with genetic instability. In our methods, covariates are incorporated through a possibly mis-specified working model and sampling variabilities of estimators are approximated using a resampling method that is based on perturbing observed processes. Our proposal, which is applicable to partial, entire or multiple chromosomes, is illustrated through application to aCGH studies of two brain tumor types, meningioma and glioma.

Remote supervision of IV-tPA for acute ischemic stroke by telemedicine or telephone before transfer to a regional stroke center is feasible and safe

Pervez, M. A., Silva, G., Masrur, S., Betensky, R., Furie, K. L., Hidalgo, R., Lima, F., Rosenthal, E. S., Rost, N., Viswanathan, A., & Schwamm, L. H. (n.d.).

Publication year

2010

Journal title

Stroke

Volume

41

Issue

1

Page(s)

e18-e24

10.1161/STROKEAHA.109.560169

Abstract

Abstract

BACKGROUND AND PURPOSE-: Because of a shortage of stroke specialists, many outlying or "spoke" hospitals initiate intravenous (IV) thrombolysis using telemedicine or telephone consultation before transferring patients to a regional stroke center (RSC) hub. We analyzed complications and outcomes of patients treated with IV tissue plasminogen activator (tPA) using the "drip and ship" approach compared to those treated directly at the RSC. METHODS-: A retrospective review of our Get With the Guidelines Stroke (GWTG-Stroke) database from 01/2003 to 03/2008 identified 296 patients who received IV tPA within 3 hours of symptom onset without catheter-based reperfusion. GWTG-Stroke definitions for symptomatic intracranial (sICH), systemic hemorrhage, discharge functional status, and destination were applied. Follow-up modified Rankin Score was recorded when available. RESULTS-: Of 296 patients, 181 (61.1%) had tPA infusion started at an outside spoke hospital (OSH) and 115 (38.9%) at the RSC hub. OSH patients were younger with fewer severe strokes than RSC patients. Patients treated based on telestroke were more frequently octogenarians than patients treated based on a telephone consult. Mortality, sICH, and functional outcomes were not different between OSH versus RSC and telephone versus telestroke patients. Among survivors, mean length of stay was shorter for OSH patients but discharge status was similar and 75% of patients walked independently at discharge. CONCLUSIONS-: Outcomes in OSH "drip and ship" patients treated in a hub-and-spoke network were comparable to those treated directly at an RSC. These data suggest that "drip and ship" is a safe and effective method to shorten time to treatment with IV tPA.

Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy

Dierksen, G. A., Skehan, M. E., Khan, M. A., Jeng, J., Nandigam, R. N., Becker, J. A., Kumar, A., Neal, K. L., Betensky, R., Frosch, M. P., Rosand, J., Johnson, K. A., Viswanathan, A., Salat, D. H., & Greenberg, S. M. (n.d.).

Publication year

2010

Journal title

Annals of Neurology

Volume

68

Issue

4

Page(s)

545-548

10.1002/ana.22099

Abstract

Abstract

Advanced cerebrovascular β-amyloid deposition (cerebral amyloid angiopathy, CAA) is associated with cerebral microbleeds, but the precise relationship between CAA burden and microbleeds is undefined. We used T2*-weighted magnetic resonance imaging (MRI) and noninvasive amyloid imaging with Pittsburgh Compound B (PiB) to analyze the spatial relationship between CAA and microbleeds. On coregistered positron emission tomography (PET) and MRI images, PiB retention was increased at microbleed sites compared to simulated control lesions (p = 0.002) and declined with increasing distance from the microbleed (p < 0.0001). These findings indicate that microbleeds occur preferentially in local regions of concentrated amyloid and support therapeutic strategies aimed at reducing vascular amyloid deposition.

A classic twin study of external ear malformations, including microtia

Artunduaga, M. A., Quintanilla-Dieck, M. D., Greenway, S., Betensky, R., Nicolau, Y., Hamdan, U., Jarrin, P., Osorno, G., Brent, B., Eavey, R., Seidman, C., & Seidman, J. G. (n.d.).

Publication year

2009

Journal title

New England Journal of Medicine

Volume

361

Issue

12

Page(s)

1216-1218

10.1056/NEJMc0902556

Abstract

Abstract

~

A latent class model with hidden markov dependence for array CGH data

Desantis, S. M., Houseman, E. A., Coull, B. A., Louis, D. N., Mohapatra, G., & Betensky, R. (n.d.).

Publication year

2009

Journal title

Biometrics

Volume

65

Issue

4

Page(s)

1296-1305

10.1111/j.1541-0420.2009.01226.x

Abstract

Abstract

Array CGH is a high-throughput technique designed to detect genomic alterations linked to the development and progression of cancer. The technique yields fluorescence ratios that characterize DNA copy number change in tumor versus healthy cells. Classification of tumors based on aCGH profiles is of scientific interest but the analysis of these data is complicated by the large number of highly correlated measures. In this article, we develop a supervised Bayesian latent class approach for classification that relies on a hidden Markov model to account for the dependence in the intensity ratios. Supervision means that classification is guided by a clinical endpoint. Posterior inferences are made about class-specific copy number gains and losses. We demonstrate our technique on a study of brain tumors, for which our approach is capable of identifying subsets of tumors with different genomic profiles, and differentiates classes by survival much better than unsupervised methods.

Application of signal processing techniques for estimating regions of copy number variations in human meningioma DNA

Stamoulis, C., Betensky, R., Mohapatra, G., & Louis, D. N. (n.d.).

Publication year

2009

Page(s)

6973-6976

10.1109/IEMBS.2009.5333851

Abstract

Abstract

We applied mode-decomposition and matched-filtering, both signal processing techniques used to increase the signal-to-noise ratio (SNR), to array CGH data of human meningioma DNA, in order to extract genomic regions of copy-number changes potentially associated with tumor progression. DNA segments from different chromosomes were decomposed into a small number of dominant components (modes), and low-amplitude modes were eliminated. The SNR of the entire segment was increased and it was possible to identify local changes in the data spatial structure, previously indistinguishable due to noise. We applied matched-filtering to the mode-reduced signals, using a normal DNA sequences (averaged over 50 healthy donors) as the template. The residual signals from this process were analyzed to identify disease-related copy number changes. We were able to identify distinct local changes at different chromosomes in patients with recurrent versus primary meningiomas.

Bone involvement predicts poor outcome in atypical meningioma : Clinical article

Gabeau-Lacet, D., Aghi, M., Betensky, R., Barker, F. G., Loeffler, J. S., & Louis, D. N. (n.d.).

Publication year

2009

Journal title

Journal of Neurosurgery

Volume

111

Issue

3

Page(s)

464-471

10.3171/2009.2.JNS08877

Abstract

Abstract

Object. The authors identified clinical features associated with progression and death in atypical meningioma (AM). Methods. Forty-seven cases of primary AM treated at Massachusetts General Hospital were retrospectively evaluated for clinical features. Associations with progression-free survival (PFS) and overall survival were assessed. Results. The estimated median PFS was 56 months (95% CI 35 months-not estimable). The overall 3- and 5-year PFS rates were 65% (95% CI 44-80%) and 48% (95% CI 26-67%), respectively. The median survival time and 5- and 10-year survival rates were 158 months (95% CI 103 months-not estimable), and 86% (95% CI 69-94%) and 61% (95% CI 35-79%), respectively. Subtotal resection was associated with increased rate of progression compared to gross-total resection (p = 0.05) and trended toward an association with decreased survival (p = 0.09). Bone involvement was associated with an increased rate of disease progression (p = 0.001) and decreased survival (p = 0.04). Bone involvement remained significantly associated with progression after Bonferroni adjustment for multiple comparisons (p = 0.008) and in bivariate Cox regression models. Seventy-eight percent of patients with bone involvement at primary diagnosis had tumor recurrence within bone, whereas only 25% of patients without evidence of bone invasion at primary diagnosis experienced osseous recurrence. Conclusions. Osseous involvement is associated with a poor outcome in patients with AMs; bone assessment is therefore extremely important. Further investigation is warranted to assess the effectiveness of bone resection and/or bone-directed radiation therapy in improving outcome.

Creatinine as the gold standard for kidney injury biomarker studies

Waikar, S. S., Betensky, R., & Bonventre, J. V. (n.d.).

Publication year

2009

Journal title

Nephrology Dialysis Transplantation

Volume

24

Issue

11

Page(s)

3263-3265

10.1093/ndt/gfp428

Abstract

Abstract

~

Genetic determinants of hearing loss associated with vestibular schwannomas

Stankovic, K. M., Mrugala, M. M., Martuza, R. L., Silver, M., Betensky, R., Nadol, J. B., & Stemmer-Rachamimov, A. O. (n.d.).

Publication year

2009

Journal title

Otology and Neurotology

Volume

30

Issue

5

Page(s)

661-667

10.1097/MAO.0b013e3181a66ece

Abstract

Abstract

HYPOTHESIS: 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.

Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas

Shen, Y., Nunes, F., Stemmer-Rachamimov, A., James, M., Mohapatra, G., Plotkin, S., Betensky, R., Engler, D. A., Roy, J., Ramesh, V., & Gusella, J. F. (n.d.).

Publication year

2009

Journal title

BMC Medical Genomics

Volume

2

10.1186/1755-8794-2-42

Abstract

Abstract

Background. Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the NF2 locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas. Methods. We compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH). Results. Sporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the NF2 tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors. Conclusion. Genomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.

Genomic profiling of atypical meningiomas associates gain of 1q with poor clinical outcome

Gabeau-Lacet, D., Engler, D., Gupta, S., Scangas, G. A., Betensky, R., Barker, F. G., Loeffler, J. S., Louis, D. N., & Mohapatra, G. (n.d.).

Publication year

2009

Journal title

Journal of Neuropathology and Experimental Neurology

Volume

68

Issue

10

Page(s)

1155-1165

10.1097/NEN.0b013e3181ba3952

Abstract

Abstract

Atypical meningiomas exhibit heterogeneous clinical outcomes. It is unclear which atypical meningiomas require aggressive multimodality treatment with surgery and radiation therapy versus surgery alone to prevent recurrence. Detailed molecular-genetic characterization of these neoplasms is necessary to understand their pathogenesis and identify clinically relevant genetic markers. Oligonucleotide array comparative genomic hybridization was used to identify frequent genetic alterations in 47 primary atypical meningiomas resected at Massachusetts General Hospital between August 1987 and September 2006. Eighty-five percent of samples exhibited loss of 22q, including the neurofibromatosis type 2 gene. The second most frequent regions of loss were confined to the short arm of chromosome 1, particularly 1p33-p36.2 (70%) and 1p13.2 (64%). Other frequent regions of loss, detected in more than 50% of samples, included 14q, 10q, 8q, 7p, 21q, 19, 9q34, and 4p16. Frequent regions of gain were detected along 1q (59%), 17q (44%), 9q34 (30%), and 7q36 (26%). Univariate marker-by-marker analysis of all frequently identified copy number alterations showed potential correlation between gain of 1q and shorter progression-free survival. Given the heterogeneous treatment outcomes of atypical meningioma, investigation of large-scale and focal genomic alterations in multi-institutional efforts may help clarify molecular-genetic signatures of clinical use.

High-dose methotrexate for elderly patients with primary CNS lymphoma

Zhu, J. J., Gerstner, E. R., Engler, D. A., Mrugala, M. M., Nugent, W., Nierenberg, K., Hochberg, F. H., Betensky, R., & Batchelor, T. T. (n.d.).

Publication year

2009

Journal title

Neuro-Oncology

Volume

11

Issue

2

Page(s)

211-215

10.1215/15228517-2008-067

Abstract

Abstract

The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at age ≥70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m2) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrastenhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade IIV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.

Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice

Garcia-Alloza, M., Prada, C., Lattarulo, C., Fine, S., Borrelli, L. A., Betensky, R., Greenberg, S. M., Frosch, M. P., & Bacskai, B. J. (n.d.).

Publication year

2009

Journal title

Journal of Neurochemistry

Volume

109

Issue

6

Page(s)

1636-1647

10.1111/j.1471-4159.2009.06096.x

Abstract

Abstract

Cerebral amyloid angiopathy (CAA), characterized by extracellular β-amyloid peptide (Aβ) deposits in vessel walls, is present in the majority of cases of Alzheimer's disease and is a major cause of hemorrhagic stroke. Although the molecular pathways activated by vascular Aβ are poorly understood, extracellular matrix metalloproteinases (MMP) and Aβ-induced oxidative stress appear to play important roles. We adapted fluorogenic assays for MMP activity and reactive oxygen species generation for use in vivo. Using multiphoton microcopy in APPswe/PS1dE9 and Tg-2576 transgenic mice, we observed strong associations between MMP activation, oxidative stress, and CAA deposition in leptomeningeal vessels. Antioxidant treatment with α-phenyl-N-tert- butyl-nitrone reduced oxidative stress associated with CAA (∼50% reduction) without affecting MMP activation. Conversely, a selection of agents that inhibit MMP by different mechanisms of action, including minocycline, simvastatin, and GM6001, reduced not only CAA-associated MMP activation (∼30-40% reduction) but also oxidative stress (∼40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with α-phenyl-N- tert-butyl-nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Aβ-related MMP activation and oxidative stress in vivo and raise the possibility that treatment with MMP inhibitors may have beneficial effects by indirectly reducing the oxidative stress associated with CAA.

Microbleeds versus macrobleeds : Evidence for distinct entities

Greenberg, S. M., Kaveer Nandigam, R. N., Delgado, P., Betensky, R., Rosand, J., Viswanathan, A., Frosch, M. P., & Smith, E. E. (n.d.).

Publication year

2009

Journal title

Stroke

Volume

40

Issue

7

Page(s)

2382-2386

10.1161/STROKEAHA.109.548974

Abstract

Abstract

Background and Purpose-Small, asymptomatic microbleeds commonly accompany larger symptomatic macrobleeds. It is unclear whether microbleeds and macrobleeds represent arbitrary categories within a single continuum versus truly distinct events with separate pathophysiologies. Methods-We performed 2 complementary retrospective analyses. In a radiographic analysis, we measured and plotted the volumes of all hemorrhagic lesions detected by gradient-echo MRI among 46 consecutive patients with symptomatic primary lobar intracerebral hemorrhage diagnosed as probable or possible cerebral amyloid angiopathy. In a second neuropathologic analysis, we performed blinded qualitative and quantitative examinations of amyloid-positive vessel segments in 6 autopsied subjects whose MRI scans demonstrated particularly high microbleed counts (>50 microbleeds on MRI, n=3) or low microbleed counts (

Polysomy for chromosomes 1 and 19 predicts earlier recurrence in anaplastic oligodendrogliomas with concurrent 1p/19q loss

Snuderl, M., Eichler, A. F., Ligon, K. L., Vu, Q. U., Silver, M., Betensky, R., Ligon, A. H., Wen, P. Y., Louis, D. N., & Iafrate, A. J. (n.d.).

Publication year

2009

Journal title

Clinical Cancer Research

Volume

15

Issue

20

Page(s)

6430-6437

10.1158/1078-0432.CCR-09-0867

Abstract

Abstract

Purpose: Loss of chromosome arms 1p and 19q is a molecular feature of oligodendroglial tumors characterized by responsiveness to chemotherapy and a favorable prognosis. The purpose of this study was to evaluate the prognostic significance of polysomy of chromosomes 1 and 19 in the setting of 1p/19q codeletion. Experimental Design: We analyzed 64 anaplastic oligodendrogliomas with 1p/19q loss or maintenance diagnosed at Massachusetts General Hospital and Brigham and Women's Hospital from 1996 to 2005; fluorescence in situ hybridization for 1p/19q and Ki-67 immunohistochemistry was done. Polysomy was defined as more than two 1q and 19p signals in >30% of the cells with concurrent 1p/19q deletion. Tumors were divided into groups based on their 1p/19q status and compared for progression-free survival, overall survival, and 5-year survival probabilities. Results: Forty-six tumors (72%) in our cohort had 1p/19q loss and 18 (28%) had 1p/19q maintenance. Of those with loss, 19 (41%) had concurrent polysomy and 27 (59%) lacked polysomy. In agreement with previous studies, the group of anaplastic oligodendrogliomas with 1p/19q loss had significantly better progression-free survival and over-all survival than anaplastic oligodendrogliomas with 1p/19q maintenance (P = 0.0009 and P < 0.0003, respectively). Among anaplastic oligodendrogliomas with 1p/19q loss, those with polysomy showed shorter progression-free survival than those with 1p/19q loss without polysomy (P = 0.0048). Overall survival was similar in tumors with and without polysomy. The Ki-67 labeling index was not associated with polysomy and did not have prognostic significance. Conclusion: The presence of polysomy in anaplastic oligodendrogliomas with deletion of 1p/19q is a marker of earlier recurrence.

A penalized latent class model for ordinal data

Desantis, S. M., Houseman, E. A., Coull, B. A., Stemmer-Rachamimov, A., & Betensky, R. (n.d.).

Publication year

2008

Journal title

Biostatistics

Volume

9

Issue

2

Page(s)

249-262

10.1093/biostatistics/kxm026

Abstract

Abstract

Latent class models provide a useful framework for clustering observations based on several features. Application of latent class methodology to correlated, high-dimensional ordinal data poses many challenges. Unconstrained analyses may not result in an estimable model. Thus, information contained in ordinal variables may not be fully exploited by researchers. We develop a penalized latent class model to facilitate analysis of high-dimensional ordinal data. By stabilizing maximum likelihood estimation, we are able to fit an ordinal latent class model that would otherwise not be identifiable without application of strict constraints. We illustrate our methodology in a study of schwannoma, a peripheral nerve sheath tumor, that included 3 clinical subtypes and 23 ordinal histological measures.

Analysis of familial aggregation studies with complex ascertainment schemes

Matthews, A. G., Finkelstein, D. M., & Betensky, R. (n.d.).

Publication year

2008

Journal title

Statistics in Medicine

Volume

27

Issue

24

Page(s)

5076-5092

10.1002/sim.3327

Abstract

Abstract

Familial aggregation studies are a common first step in the identification of genetic determinants of disease. If aggregation is found, more refined genetic studies may be undertaken. Complex ascertainment schemes are frequently employed to ensure that the sample contains a sufficient number of families with multiple affected members, as required to detect aggregation. For example, an eligibility criterion for a family might be that both the mother and daughter have disease. Adjustments must be made for ascertainment to avoid bias. We propose adjusting for complex ascertainment schemes through a joint model for the outcomes of disease and ascertainment. This approach improves upon previous simplifying assumptions regarding the ascertainment process.