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
Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease
AbstractSerrano-Pozo, A., Mielke, M. L., Gómez-Isla, T., Betensky, R. A., Growdon, J. H., Frosch, M. P., & Hyman, B. T. (n.d.).Publication year
2011Journal title
American Journal of PathologyVolume
179Issue
3Page(s)
1373-1384AbstractSenile 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
AbstractMcDaniel, S., Minnier, J., Betensky, R. A., Mohapatra, G., Shen, Y., Gusella, J. F., Louis, D. N., & Cai, T. (n.d.).Publication year
2010Journal title
Statistics in BiosciencesVolume
2Issue
2Page(s)
120-136AbstractTumoral 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
AbstractPervez, M. A., Silva, G., Masrur, S., Betensky, R. A., Furie, K. L., Hidalgo, R., Lima, F., Rosenthal, E. S., Rost, N., Viswanathan, A., & Schwamm, L. H. (n.d.).Publication year
2010Journal title
StrokeVolume
41Issue
1Page(s)
e18-e24AbstractBACKGROUND 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
AbstractDierksen, G. A., Skehan, M. E., Khan, M. A., Jeng, J., Nandigam, R. N., Becker, J. A., Kumar, A., Neal, K. L., Betensky, R. A., Frosch, M. P., Rosand, J., Johnson, K. A., Viswanathan, A., Salat, D. H., & Greenberg, S. M. (n.d.).Publication year
2010Journal title
Annals of NeurologyVolume
68Issue
4Page(s)
545-548AbstractAdvanced 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.). In New England Journal of Medicine (1–).Publication year
2009Volume
361Issue
12Page(s)
1216-1218A latent class model with hidden markov dependence for array CGH data
AbstractDesantis, S. M., Houseman, E. A., Coull, B. A., Louis, D. N., Mohapatra, G., & Betensky, R. A. (n.d.).Publication year
2009Journal title
BiometricsVolume
65Issue
4Page(s)
1296-1305AbstractArray 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.Bone involvement predicts poor outcome in atypical meningioma: Clinical article
AbstractGabeau-Lacet, D., Aghi, M., Betensky, R. A., Barker, F. G., Loeffler, J. S., & Louis, D. N. (n.d.).Publication year
2009Journal title
Journal of NeurosurgeryVolume
111Issue
3Page(s)
464-471AbstractObject. 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.Genetic determinants of hearing loss associated with vestibular schwannomas
AbstractStankovic, K. M., Mrugala, M. M., Martuza, R. L., Silver, M., Betensky, R. A., 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.Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas
AbstractShen, Y., Nunes, F., Stemmer-Rachamimov, A., James, M., Mohapatra, G., Plotkin, S., Betensky, R. A., Engler, D. A., Roy, J., Ramesh, V., & Gusella, J. F. (n.d.).Publication year
2009Journal title
BMC Medical GenomicsVolume
2AbstractBackground. 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
AbstractGabeau-Lacet, D., Engler, D., Gupta, S., Scangas, G. A., Betensky, R. A., Barker, F. G., Loeffler, J. S., Louis, D. N., & Mohapatra, G. (n.d.).Publication year
2009Journal title
Journal of Neuropathology and Experimental NeurologyVolume
68Issue
10Page(s)
1155-1165AbstractAtypical 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
AbstractZhu, J. J., Gerstner, E. R., Engler, D. A., Mrugala, M. M., Nugent, W., Nierenberg, K., Hochberg, F. H., Betensky, R. A., & Batchelor, T. T. (n.d.).Publication year
2009Journal title
Neuro-OncologyVolume
11Issue
2Page(s)
211-215AbstractThe 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
AbstractGarcia-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
2009Journal title
Journal of NeurochemistryVolume
109Issue
6Page(s)
1636-1647AbstractCerebral 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
AbstractGreenberg, S. M., Kaveer Nandigam, R. N., Delgado, P., Betensky, R. A., Rosand, J., Viswanathan, A., Frosch, M. P., & Smith, E. E. (n.d.).Publication year
2009Journal title
StrokeVolume
40Issue
7Page(s)
2382-2386AbstractBackground 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 (<3 microbleeds, n=3). Results-Plotted on a logarithmic scale, the volumes of 163 hemorrhagic lesions identified on scans from the 46 subjects fell in a distinctly bimodal distribution with mean volumes for the 2 modes of 0.009 cm 3 and 27.5 cm 3. The optimal cut point for separating the 2 peaks (determined by receiver operating characteristics) corresponded to a lesion diameter of 0.57 cm. On neuropathologic analysis, the high microbleed-count autopsied subjects showed significantly thicker amyloid-positive vessel walls than the low microbleed-count subjects (proportional wall thickness 0.53±0.01 versus 0.37±0.01; P<0.0001; n=333 vessel segments analyzed). Conclusions-These findings suggest that cerebral amyloid angiopathy-associated microbleeds and macrobleeds comprise distinct entities. Increased vessel wall thickness may predispose to formation of microbleeds relative to macrobleeds.Polysomy for chromosomes 1 and 19 predicts earlier recurrence in anaplastic oligodendrogliomas with concurrent 1p/19q loss
AbstractSnuderl, M., Eichler, A. F., Ligon, K. L., Vu, Q. U., Silver, M., Betensky, R. A., Ligon, A. H., Wen, P. Y., Louis, D. N., & Iafrate, A. J. (n.d.).Publication year
2009Journal title
Clinical Cancer ResearchVolume
15Issue
20Page(s)
6430-6437AbstractPurpose: 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
AbstractDesantis, S. M., Houseman, E. A., Coull, B. A., Stemmer-Rachamimov, A., & Betensky, R. A. (n.d.).Publication year
2008Journal title
BiostatisticsVolume
9Issue
2Page(s)
249-262AbstractLatent 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
AbstractMatthews, A. G., Finkelstein, D. M., & Betensky, R. A. (n.d.).Publication year
2008Journal title
Statistics in MedicineVolume
27Issue
24Page(s)
5076-5092AbstractFamilial 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.Estimating time-to-event from longitudinal ordinal data using random-effects Markov models: Application to multiple sclerosis progression
AbstractMandel, M., & Betensky, R. A. (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.Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas
AbstractPatil, S., Perry, A., MacCollin, M., Dong, S., Betensky, R. A., Yeh, T. H., Gutmann, D. H., & Stemmer-Rachamimov, A. O. (n.d.).Publication year
2008Journal title
Brain PathologyVolume
18Issue
4Page(s)
517-519AbstractThe INI1/SMARCB1 protein product (INI1), a component of a transcription complex, was recently implicated in the pathogenesis of schwannomas in two members of a single family with familial schwannomatosis. Tumors were found to have both constitutional and somatic mutations of the SMARCB1 gene and showed a mosaic pattern of loss of INI1 expression by immunohistochemistry, suggesting a tumor composition of mixed null and haploinsufficient cells. To determine if this finding could be extended to all tumors arising in familial schwannomatosis, and how it compares with other multiple schwannoma syndromes [sporadic schwannomatosis and neurofibromatosis 2 (NF2)] as well as to sporadic, solitary schwannomas, we performed an immunohistochemistry analysis on 45 schwannomas from patients with multiple schwannoma syndromes and on 38 solitary, sporadic schwannomas from non-syndromic patients. A mosaic pattern of INI1 expression was seen in 93% of tumors from familial schwannomatosis patients, 55% of tumors from sporadic schwannomatosis, 83% of NF2-associated tumors and only 5% of solitary, sporadic schwannomas. These results confirm a role for INI1/SMARCB1 in multiple schwannoma syndromes and suggest that a different pathway of tumorigenesis occurs in solitary, sporadic tumors.Predicting clinical progression in multiple sclerosis with the magnetic resonance disease severity scale
AbstractBakshi, R., Neema, M., Healy, B. C., Liptak, Z., Betensky, R. A., Buckle, G. J., Gauthier, S. A., Stankiewicz, J., Meier, D., Egorova, S., Arora, A., Guss, Z. D., Glanz, B., Khoury, S. J., Guttmann, C. R., & Weiner, H. L. (n.d.).Publication year
2008Journal title
Archives of NeurologyVolume
65Issue
11Page(s)
1449-1453AbstractPrevious Presentation: This study was presented at the 59th annual meeting of the American Academy of Neurology; May 1, 2007; Boston, Massachusetts. Background: Individual magnetic resonance imaging (MRI) disease severity measures, such as atrophy or lesions, show weak relationships to clinical status in patients with multiple sclerosis (MS). Objective: To combine MS-MRI measures of disease severity into a composite score. Design: Retrospective analysis of prospectively collected data. Setting: Community-based and referral subspecialty clinic in an academic hospital. Patients: A total of 103 patients with MS, with a mean (SD) Expanded Disability Status Scale (EDSS) score of 3.3 (2.2), of whom 62 (60.2%) had the relapsing-remitting, 33 (32.0%) the secondary progressive, and 8 (7.8%) the primary progressive form. Main Outcome Measures: Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV (T1:T2) assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1:T2. Results: The MRDSS score averaged 5.1 (SD, 2.6). Baseline MRI and EDSS correlations were moderate for BPF, T1:T2, and MRDSS and weak for T2LV. The MRDSS showed a larger effect size than the individual MRI components in distinguishing patients with the relapsingremitting form from those with the secondary progressive form. Models containing either T2LV or MRDSS were significantly associated with disability progression during the mean (SD) 3.2 (0.3)-year observation period, when adjusting for baseline EDSS score. Conclusion: Combining brain MRI lesion and atrophy measures can predict MS clinical progression and provides the basis for developing an MRI-based continuous scale as a marker of MS disease severity.Prognostic value of tumor microinvasion and metalloproteinases expression in intracranial pediatric ependymomas
AbstractSnuderl, M., Chi, S. N., De Santis, S. M., Stemmer-Rachamimov, A. O., Betensky, R. A., De Girolami, U., & Kieran, M. W. (n.d.).Publication year
2008Journal title
Journal of Neuropathology and Experimental NeurologyVolume
67Issue
9Page(s)
911-920AbstractEpendymomas are common pediatric intracranial neoplasms that often appear well circumscribed on imaging but may recur when they are treated by surgical resection alone. The current World Health Organization histological grading system does not accurately predict clinical behavior. The aim of this study was to identify histological and immunohistochemical features that correlate with clinical course in patients with ependymomas treated by gross total resection. We analyzed 41 pediatric ependymomas for microinvasion and correlated immunostaining for the metalloproteinase (MMP)-2 and MMP14 and for ezrin and bcl-2 with clinical outcome. Gross total resection had a significantly positive effect on overall survival and progression-free survival. In 28 patients who underwent gross total resection, microinvasion correlated with poor overall survival (p = 0.003) and progression-free survival (p = 0.03). Gross totally resected tumors with high expression of MMP2 and MMP14 had significantly shorter overall survival. Ezrin staining identified tumor cells invading the adjacent white matter that were not identified by routine stains, but Ezrin staining and bcl-2 staining did not provide strong prognostic correlations. The data indicate that tumor microinvasion into adjacent brain and tumor expression of MMP2 and MMP14 predict both overall and progression-free survival in pediatric ependymomas, and these are useful prognostic markers that may help stratify patients for adjuvant therapies.Simultaneous confidence intervals based on the percentile bootstrap approach
AbstractMandel, M., & Betensky, R. A. (n.d.).Publication year
2008Journal title
Computational Statistics and Data AnalysisVolume
52Issue
4Page(s)
2158-2165AbstractThis note concerns the construction of bootstrap simultaneous confidence intervals (SCI) for m parameters. Given B bootstrap samples, we suggest an algorithm with complexity of O (mB log (B)). We apply our algorithm to construct a confidence region for time dependent probabilities of progression in multiple sclerosis and for coefficients in a logistic regression analysis. Alternative normal based simultaneous confidence intervals are presented and compared to the bootstrap intervals.Topotecan as salvage therapy for relapsed or refractory primary central nervous system lymphoma
AbstractVoloschin, A. D., Betensky, R., Wen, P. Y., Hochberg, F., & Batchelor, T. (n.d.).Publication year
2008Journal title
Journal of Neuro-OncologyVolume
86Issue
2Page(s)
211-215AbstractTreatment for patients with refractory or relapsed primary CNS lymphoma (PCNSL) remains unsatisfactory. Topotecan is an intravenous topoisomerase I inhibitor with good CSF penetration and documented efficacy in patients with relapsed systemic non-Hodgkin's lymphoma. In this study 15 patients with refractory or relapsed PCNSL were treated with intravenous topotecan (1.5 mg/m2) for five consecutive days during each 21-day cycle. All 15 patients had measurable, contrast-enhancing tumor on cranial MRI at the time of relapse. Three (20%) patients achieved a complete response after one, three and four cycles, respectively, while three (20%) patients achieved a partial response after two cycles each, for a total response proportion of 40%. Three patients had stable disease at the end of topotecan treatment. Six patients (40%) had progressive disease during treatment. Median overall survival was 981 days (95% CI: 275, NA) and median progression free survival was 60 days (95% CI: 46, 945). Three out of 15 patients had grade 3 thrombocytopenia. Six out of 15 patients had grade 3 neutropenia, while 5/15 patients had grade 4 neutropenia, and 13/15 patients received g-CSF at some point during treatment. There were no deaths directly related to treatment toxicity. Our study shows that topotecan, as a salvage therapy in patients with relapsed or refractory PCNSL, is associated with an overall response proportion of 40% and should be considered in patients who have failed prior methotrexate-based chemotherapy and/or whole brain irradiation. However, progression is frequent and early and most patients required growth factor support due to myelotoxicity.Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans
AbstractVaidya, V. S., Waikar, S. S., Ferguson, M. A., Collings, F. B., Sunderland, K., Gioules, C., Bradwin, G., Matsouaka, R., Betensky, R. A., Curhan, G. C., & Bonventre, J. V. (n.d.).Publication year
2008Journal title
Clinical and translational scienceVolume
1Issue
3Page(s)
200-208AbstractAcute kidney injury (AKI) is associated with high morbidity and mortality. The lack of sensitive and specific injury biomarkers has greatly impeded the development of therapeutic strategies to improve outcomes of AKI. The unique objective of this study was to evaluate the diagnostic performance of nine urinary biomarkers of AKI-kidney injury molecule-1 (KIM-1), neutrophil gelatinase associated lipocalin (NGAL), interleukin-18 (IL-18), hepatocyte growth factor (HGF), cystatin C (Cys), N-acetyl-β-D-glucosaminidase (NAG), vascular endothelial growth factor (VEGF), chemokine interferon-inducible protein 10 (IP-10; CXCL10), and total protein-in a cross-sectional comparison of 204 patients with or without AKI. Median urinary concentrations of each biomarker were significantly higher in patients with AKI than in those without AKI (p < 0.001). The area under the receiver operating characteristics curve (AUC-ROC) for the combination of biomarkers using a logic regression model [risk score of 2.93*(NGAL > 5.72 and HGF > 0.17) + 2.93*(PROTEIN > 0.22) -2*(KIM < 0.58)] was greater (0.94) than individual biomarker AUC-ROCs. Age-adjusted levels of urinary KIM-1, NAG, HGF, VEGF, and total protein were significantly higher in patients who died or required renal replacement therapy (RRT) when compared to those who survived and did not require RRT. Our results demonstrate the comparative value of multiple biomarkers in the diagnosis and prognosis of AKI.Urinary biomarkers in the early diagnosis of acute kidney injury
AbstractHan, W. K., Waikar, S. S., Johnson, A., Betensky, R. A., Dent, C. L., Devarajan, P., & Bonventre, J. V. (n.d.).Publication year
2008Journal title
Kidney InternationalVolume
73Issue
7Page(s)
863-869AbstractA change in the serum creatinine is not sensitive for an early diagnosis of acute kidney injury. We evaluated urinary levels of matrix metalloproteinase-9 (MMP-9), N-acetyl-β-D-glucosaminidase (NAG), and kidney injury molecule-1 (KIM-1) as biomarkers for the detection of acute kidney injury. Urine samples were collected from 44 patients with various acute and chronic kidney diseases, and from 30 normal subjects in a cross-sectional study. A case-control study of children undergoing cardio-pulmonary bypass surgery included urine specimens from each of 20 patients without and with acute kidney injury. Injury was defined as a greater than 50% increase in the serum creatinine within the first 48 h after surgery. The biomarkers were normalized to the urinary creatinine concentration at 12, 24, and 36 h after surgery with the areas under the receiver-operating characteristic curve compared for performance. In the cross-sectional study, the area under the curve for MMP-9 was least sensitive followed by KIM-1 and NAG. Combining all three biomarkers achieved a perfect score diagnosing acute kidney injury. In the case-control study, KIM-1 was better than NAG at all time points, but combining both was no better than KIM-1 alone. Urinary MMP-9 was not a sensitive marker in the case-control study. Our results suggest that urinary biomarkers allow diagnosis of acute kidney injury earlier than a rise in serum creatinine.Antibody-mediated clearance of amyloid-β peptide from cerebral amyloid angiopathy revealed by quantitative in vivo imaging
AbstractPrada, C. M., Garcia-Alloza, M., Betensky, R. A., Zhang-Nunes, S. X., Greenberg, S. M., Bacskai, B. J., & Frosch, M. P. (n.d.).Publication year
2007Journal title
Journal of NeuroscienceVolume
27Issue
8Page(s)
1973-1980AbstractCerebral amyloid angiopathy (CAA) is the accumulation of amyloid-β peptide (Aβ) in the vessel wall of arteries in the brain. Because CAA is commonly associated with Alzheimer's disease (AD), characterized by parenchymal deposition of the same peptide in the form of senile plaques, there is considerable interest in the relationship of the two deposits in generating human disease. The study of CAA is of particular importance for immunotherapeutic approaches to AD, because reports of anti-Aβ immunotherapy in mice and humans have suggested that, whereas CAA appeared resistant to clearance, its response to this treatment promoted potential adverse effects, including meningoencephalitis. We used multiphoton microscopy and longitudinal imaging to monitor CAA in a mouse model of amyloid deposition to evaluate the effects of anti-Aβ passive immunotherapy. We found detectable clearance of CAA deposits within 1 week after a single administration of antibody directly to the brain, an effect that was short-lived. Chronic administration of antibody over 2 weeks led to more robust clearance without evidence of hemorrhage or other destructive changes. We found that the progressive clearance of Aβ from vessels follows distinct kinetics from what has been previously reported for clearance of plaques (parenchymal deposits of Aβ). This quantitative in vivo imaging approach directly demonstrates that CAA in a transgenic mouse model can be cleared with an optimized immunotherapy.