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

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.

Power and sample size calculations for the Wilcoxon-Mann-Whitney test in the presence of death-censored observations

Matsouaka, R. A., & Betensky, R. (n.d.).

Publication year

2015

Journal title

Statistics in Medicine

Volume

34

Issue

3

Page(s)

406-431

10.1002/sim.6355

Abstract

Abstract

We consider a clinical trial of a potentially lethal disease in which patients are randomly assigned to two treatment groups and are followed for a fixed period of time; a continuous endpoint is measured at the end of follow-up. For some patients; however, death (or severe disease progression) may preclude measurement of the endpoint. A statistical analysis that includes only patients with endpoint measurements may be biased. An alternative analysis includes all randomized patients, with rank scores assigned to the patients who are available for the endpoint measurement on the basis of the magnitude of their responses and with 'worst-rank' scores assigned to those patients whose death precluded the measurement of the continuous endpoint. The worst-rank scores are worse than all observed rank scores. The treatment effect is then evaluated using the Wilcoxon-Mann-Whitney test. In this paper, we derive closed-form formulae for the power and sample size of the Wilcoxon-Mann-Whitney test when missing measurements of the continuous endpoints because of death are replaced by worst-rank scores. We distinguish two approaches for assigning the worst-rank scores. In the tied worst-rank approach, all deaths are weighted equally, and the worst-rank scores are set to a single value that is worse than all measured responses. In the untied worst-rank approach, the worst-rank scores further rank patients according to their time of death, so that an earlier death is considered worse than a later death, which in turn is worse than all measured responses. In addition, we propose four methods for the implementation of the sample size formulae for a trial with expected early death. We conduct Monte Carlo simulation studies to evaluate the accuracy of our power and sample size formulae and to compare the four sample size estimation methods.

Power Calculations for Familial Aggregation Studies

Rabbee, N., & Betensky, R. (n.d.).

Publication year

2004

Journal title

Genetic Epidemiology

Volume

26

Issue

4

Page(s)

316-327

10.1002/gepi.10312

Abstract

Abstract

Family studies are frequently undertaken as the first step in the search for genetic determinants of disease. Significant familial aggregation of disease is suggestive of a genetic etiology for the disease, and may lead to more focused genetic analyses. Many methods have been proposed in the literature for the analysis of family studies. One model that is appealing for its simplicity of computation and the conditional interpretation of its parameters is the quadratic exponential model (e.g., Zhao and Prentice [1990] Biometrika 77:642-648; Betensky and Whittemore [1996] Appl. Stat. 45:422-429; Hudson et al. [2001a] Am. J. Epidemiol. 153:500-514). However, a limiting factor in its application, as well as that of the other proposed methods, is that power and sample size calculations have not been derived. These calculations are essential for investigators who are designing family studies. Here we derive analytic approximations for power for testing for familial aggregation, for both randomly sampled and nonrandomly sampled families. We also present simulation studies of power for both single- and two-disease cases, both under random and nonrandom sampling.

Prediagnostic adult body mass index change and esophageal adenocarcinoma survival

Loehrer, E. A., Giovannucci, E. L., Betensky, R., Shafer, A., & Christiani, D. C. (n.d.).

Publication year

2020

Journal title

Cancer Medicine

Volume

9

Issue

10

Page(s)

3613-3622

10.1002/cam4.3015

Abstract

Abstract

Background: We examined whether body mass index (BMI) changes in adulthood, prior to disease onset, are associated with overall survival among esophageal adenocarcinoma patients. Methods: We included 285 histologically confirmed patients with a complete baseline BMI questionnaire. Using extended Cox regression models, we obtained adjusted hazard ratios (HRs) for the associations between overall survival and BMI at diagnosis, BMI 6 months before diagnosis, self-reported average adult BMI, and ΔBMI (BMI 6 months before diagnosis minus average adult BMI), categorized into tertiles

Predicting clinical progression in multiple sclerosis with the magnetic resonance disease severity scale

Bakshi, R., Neema, M., Healy, B. C., Liptak, Z., Betensky, R., 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

2008

Journal title

Archives of Neurology

Volume

65

Issue

11

Page(s)

1449-1453

10.1001/archneur.65.11.1449

Abstract

Abstract

Previous 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.

Predicting in vitro fertilization live birth using stimulation day 6 estradiol, age, and follicle-stimulating hormone

Srouji, S. S., Mark, A., Levine, Z., Betensky, R., Hornstein, M. D., & Ginsburg, E. S. (n.d.).

Publication year

2005

Journal title

Fertility and Sterility

Volume

84

Issue

3

Page(s)

795-797

10.1016/j.fertnstert.2005.02.042

Abstract

Abstract

A retrospective analysis of IVF data was performed to determine predictors of live birth rate in four common stimulation protocols. A combination of day 6 E2 levels, age, and day 3 FSH levels can be used to predict cycle outcome.

Predicting short-term disability in multiple sclerosis

Betensky, R., Gauthier, S. A., Mandel, M., Guttmann, C. R., Glanz, B. I., Khoury, S. J., Betensky, R. A., & Weiner, H. L. (n.d.).

Publication year

2007

Journal title

Neurology

Volume

68

Issue

24

Page(s)

2059-2065

10.1212/01.wnl.0000264890.97479.b1

Abstract

Abstract

OBJECTIVE: To develop covariate specific short-term disability curves to demonstrate the probability of progressing by Expanded Disability Status Scale (EDSS) at semiannual visits. METHODS: Semiannual EDSS scores were prospectively collected in 218 relapsing-remitting (RR) and clinically isolated syndrome (CIS) patients as part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. Baseline brain parenchymal fraction (BPF) and T2 lesion volume were available on 205 patients. A partial proportional odds model determined the influence of covariates on the change in EDSS score at subsequent visits. A discrete second order Markov transitional model was fit and generated a probability matrix for each subject; the 6-month probabilities of EDSS change were graphically represented. RESULTS: The univariate analysis demonstrated the lowest baseline BPF quartile (OR 1.99; p = 0.0203) and the highest T2 lesion volume quartile (OR 2.19; p = 0.0130) were associated with progression in EDSS. Covariate specific disability curves demonstrated the effect of BPF and T2 lesion volume on short-term progression. In subjects with a 6-month EDSS of 2, the probability of a sustained progression of an EDSS of 3 within 3 years was 0.277 for a subject with low BPF and a high T2 lesion volume vs 0.055 for a subject with high BPF and a low T2 lesion volume. CONCLUSIONS: Markov transitional models allow for the comparison of covariate specific short-term disability changes among groups of patients with multiple sclerosis.

Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy

Gurol, M. E., Dierksen, G., Betensky, R., Gidicsin, C., Halpin, A., Becker, A., Carmasin, J., Ayres, A., Schwab, K., Viswanathan, A., Salat, D., Rosand, J., Johnson, K. A., & Greenberg, S. M. (n.d.).

Publication year

2012

Journal title

Neurology

Volume

79

Issue

4

Page(s)

320-326

10.1212/WNL.0b013e31826043a9

Abstract

Abstract

We aimed to determine whether amyloid imaging can help predict the location and number of future hemorrhages in cerebral amyloid angiopathy (CAA). We performed a longitudinal cohort study of 11 patients with CAA without dementia who underwent serial brain MRIs after baseline amyloid imaging with Pittsburgh compound B (PiB). Mean distribution volume ratio (DVR) of PiB was determined at the sites of new micro/macrobleeds identified on follow-up MRI and compared with PiB retention at “simulated” hemorrhages, randomly placed in the same subjects using a probability distribution map of CAA-hemorrhage location. Mean PiB retention at the sites of observed new bleeds was also compared to that in shells concentrically surrounding the bleeds. Finally the association between number of incident bleeds and 3 regional amyloid measures were obtained. Nine of 11 subjects had at least one new microbleed on follow-up MRI (median 4, interquartile range [IQR] 1-9) and 2 had 5 new intracerebral hemorrhages. Mean DVR was greater at the sites of incident bleeds (1.34, 95% confidence interval [CI] 1.23-1.46) than simulated lesions (1.14, 95% CI 1.07-1.22, p < 0.0001) in multivariable models. PiB retention decreased with increasing distance from sites of observed bleeds (p < 0.0001). Mean DVR in a superior frontal/parasagittal region of interest correlated independently with number of future hemorrhages after adjustment for relevant covariates (p = 0.003). Our results provide direct evidence that new CAA-related hemorrhages occur preferentially at sites of increased amyloid deposition and suggest that PiB-PET imaging may be a useful tool in prediction of incident hemorrhages in patients with CAA. Aβ: β-amyloid CAA: cerebral amyloid angiopathy CI: confidence interval DVR: distribution volume ratio IQR: interquartile range PiB: Pittsburgh compound B ROI: region of interest SWI: susceptibility-weighted imaging.

Predictive value of CD19 measurements for bacterial infections in children infected with human immunodeficiency virus

Betensky, R., Calvelli, T., & Pahwa, S. (n.d.).

Publication year

1999

Journal title

Clinical and Diagnostic Laboratory Immunology

Volume

6

Issue

2

Page(s)

247-253

10.1128/cdli.6.2.247-253.1999

Abstract

Abstract

We investigated the predictive value of CD19 cell percentages (CD19%) for times to bacterial infections, using data from six pediatric AIDS Clinical Trials Group protocols and adjusting for other potentially prognostic variables, such as CD4%, CD8%, immunoglobulin (IgA) level, lymphocyte count, prior infections, prior zidovudine treatment, and age. In addition, we explored the combined effects of CD19% and IgG level in predicting time to infection. We found that a low CD19% is associated with a nonsignificant 1.2-fold increase in hazard of bacterial infection (95% confidence interval: 0.97, 1.49). In contrast, a high IgG level is associated with a nonsignificant 0.87-fold decrease in hazard of infection (95% confidence interval: 0.68, 1.12). CD4% was more prognostic of time to bacterial infection than CD19% or IgG level. Low CD19% and high IgG levels together lead to a significant (P < 0.01) 0.50-fold decrease in hazard (95% confidence interval: 0.35, 0.73) relative to low CD19% and low IgG levels. Similarly, in a model involving assay result changes (from baseline to 6 months) as well as baseline values, the effect of CD19% by itself is reversed from its effect in conjunction with IgG. In this model, CD19% that are increasing and high are associated with decreases in hazard of infection (P < 0.01), while increasing CD19% and increasing IgG levels are associated with significant (at the P = 0.01 level) fourfold increases in hazard of infection relative to stable CD19% and decreasing; stable, or increasing IgG levels. Our data suggest that CD19%, in conjunction with IgG level, provides a useful prognostic tool for bacterial infections. It is highly likely thai T-helper function impacts on B-cell function; thus, inclusion of CD4% in such analyses may greatly enhance the assessment of risk for bacterial infection.

Predictors for the use of systemic therapy in stage IB Mycosis fungoides

Rodriguez, E., Needle, C. D., Martinez, M. J., Nohria, A., Xing, Y., Song, C., Betensky, R., Latkowski, J. A., & Adotama, P. (n.d.).

Publication year

2024

Journal title

Archives of Dermatological Research

Volume

316

Issue

6

10.1007/s00403-024-03005-0

Abstract

Abstract

Background: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is aprospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) inpatients with newly diagnosed mycosis fungoides (MF). Objectives: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB)staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. Methods: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centresin 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. Results: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smallerpercentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariateanalysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA,20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs.T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%,while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improvedsignificantly both in patients with responsive disease and in those with stable disease. Conclusions: Disease characteristics such as presence of plaques and FMF influence physician treatment choices,and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, futuretreatment guidelines for early-stage MF need to address these issues.

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.

Primary leptomeningeal lymphoma : International Primary CNS lymphoma collaborative group report

Taylor, J. W., Flanagan, E. P., O'Neill, B. P., Siegal, T., Omuro, A., DeAngelis, L., Baehring, J., Nishikawa, R., Pinto, F., Chamberlain, M., Hoang-Xuan, K., Gonzalez-Aguilar, A., Batchelor, T., Blay, J. Y., Korfel, A., Betensky, R., Lopes, M. B., & Schiff, D. (n.d.).

Publication year

2013

Journal title

Neurology

Volume

81

Issue

19

Page(s)

1690-1696

10.1212/01.wnl.0000435302.02895.f3

Abstract

Abstract

Objective: To evaluate clinical presentation, optimal diagnostic evaluation and treatment, and outcome in primary leptomeningeal lymphoma, a rare form of primary CNS lymphoma without parenchymal or systemic involvement. Methods: The International Primary CNS Lymphoma Collaborative Group, a multidisciplinary group of physicians with a particular interest in primary CNS lymphoma, retrospectively identified cases of lymphoma isolated to the leptomeninges as diagnosed by CSF cytology, flow cytometry, or biopsy, without systemic or parenchymal brain/spinal cord lymphoma or immunodeficiency. Results: Forty-eight patients were identified, with median age at diagnosis of 51 years and median Eastern Cooperative Oncology Group performance status of 2. Presenting symptoms were multifocal in 68%. Leptomeningeal enhancement was seen in 74% and CSF profile was abnormal in all cases. CSF cytology detected malignant lymphocytes in 67%. Flow cytometry identified monoclonal population in 80%, as did receptor gene rearrangement studies in 71%. Sixty-two percent had B-cell lymphoma, 19% T-cell, and 19% unclassified. Treatment varied and included fractionated radiotherapy (36%), systemic chemotherapy (78%), and intra-CSF chemotherapy (66%), with 66% receiving ≥2 modalities. Seventy-one percent had a favorable clinical response; ultimately, 44% received salvage treatment. Median overall survival was 24 months, with 11 patients still alive at 50 months follow-up. Conclusion: Primary leptomeningeal lymphoma is a rare form of primary CNS lymphoma. Patients usually present with multifocal symptoms, with evidence of leptomeningeal enhancement and diagnostic CSF analysis. Although treatment is highly variable, patients have a better prognosis than previously reported and a subset may be cured.

Probing tumor microenvironment in patients with newly diagnosed glioblastoma during chemoradiation and adjuvant temozolomide with functional MRI

Ina Ly, K., Vakulenko-Lagun, B., Emblem, K. E., Ou, Y., Da, X., Betensky, R., Kalpathy-Cramer, J., Duda, D. G., Jain, R. K., Chi, A. S., Plotkin, S. R., Batchelor, T. T., Sorensen, G., Rosen, B. R., & Gerstner, E. R. (n.d.).

Publication year

2018

Journal title

Scientific reports

Volume

8

Issue

1

10.1038/s41598-018-34820-x

Abstract

Abstract

Functional MRI may identify critical windows of opportunity for drug delivery and distinguish between early treatment responders and non-responders. Using diffusion-weighted, dynamic contrast-enhanced, and dynamic susceptibility contrast MRI, as well as pro-angiogenic and pro-inflammatory blood markers, we prospectively studied the physiologic tumor-related changes in fourteen newly diagnosed glioblastoma patients during standard therapy. 153 MRI scans and blood collection were performed before chemoradiation (baseline), weekly during chemoradiation (week 1–6), monthly before each cycle of adjuvant temozolomide (pre-C1-C6), and after cycle 6. The apparent diffusion coefficient, volume transfer coefficient (Ktrans), and relative cerebral blood volume (rCBV) and flow (rCBF) were calculated within the tumor and edema regions and compared to baseline. Cox regression analysis was used to assess the effect of clinical variables, imaging, and blood markers on progression-free (PFS) and overall survival (OS). After controlling for additional covariates, high baseline rCBV and rCBF within the edema region were associated with worse PFS (microvessel rCBF: HR = 7.849, p = 0.044; panvessel rCBV: HR = 3.763, p = 0.032; panvessel rCBF: HR = 3.984; p = 0.049). The same applied to high week 5 and pre-C1 Ktrans within the tumor region (week 5 Ktrans: HR = 1.038, p = 0.003; pre-C1 Ktrans: HR = 1.029, p = 0.004). Elevated week 6 VEGF levels were associated with worse OS (HR = 1.034; p = 0.004). Our findings suggest a role for rCBV and rCBF at baseline and Ktrans and VEGF levels during treatment as markers of response. Functional imaging changes can differ substantially between tumor and edema regions, highlighting the variable biologic and vascular state of tumor microenvironment during therapy.

Prognostic value of tumor microinvasion and metalloproteinases expression in intracranial pediatric ependymomas

Snuderl, M., Chi, S. N., De Santis, S. M., Stemmer-Rachamimov, A. O., Betensky, R., De Girolami, U., & Kieran, M. W. (n.d.).

Publication year

2008

Journal title

Journal of Neuropathology and Experimental Neurology

Volume

67

Issue

9

Page(s)

911-920

10.1097/NEN.0b013e318184f413

Abstract

Abstract

Ependymomas 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.

Pseudo-observation regression for sequentially truncated data

Betensky, R., Parner, E. T., Overgaard, M., & Qian, J. (n.d.).

Abstract

Abstract

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Pseudo-observations for bivariate survival data

Travis-Lumer, Y., Mandel, M., & Betensky, R. (n.d.).

Publication year

2025

Journal title

Biometrics

Volume

81

Issue

1

10.1093/biomtc/ujaf006

Abstract

Abstract

The pseudo-observations approach has been gaining popularity as a method to estimate covariate effects on censored survival data. It is used regularly to estimate covariate effects on quantities such as survival probabilities, restricted mean life, cumulative incidence, and others. In this work, we propose to generalize the pseudo-observations approach to situations where a bivariate failure-time variable is observed, subject to right censoring. The idea is to first estimate the joint survival function of both failure times and then use it to define the relevant pseudo-observations. Once the pseudo-observations are calculated, they are used as the response in a generalized linear model. We consider 2 common nonparametric estimators of the joint survival function: the estimator of Lin and Ying (1993) and the Dabrowska estimator (Dabrowska, 1988). For both estimators, we show that our bivariate pseudo-observations approach produces regression estimates that are consistent and asymptotically normal. Our proposed method enables estimation of covariate effects on quantities such as the joint survival probability at a fixed bivariate time point or simultaneously at several time points and, consequentially, can estimate covariate-adjusted conditional survival probabilities. We demonstrate the method using simulations and an analysis of 2 real-world datasets.

PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis

Sasaki, H., Zlatescu, M. C., Betensky, R., Ino, Y., Cairncross, J. G., & Louis, D. N. (n.d.).

Publication year

2001

Journal title

American Journal of Pathology

Volume

159

Issue

1

Page(s)

359-367

10.1016/S0002-9440(10)61702-6

Abstract

Abstract

Allelic loss of 10q is a common genetic event in malignant gliomas, with three 10q tumor suppressor genes, ERCC6, PTEN, and DMBT1, putatively implicated in the most common type of malignant glioma, glioblastoma. Anaplastic oligodendroglioma, another type of malignant glioma, provides a unique opportunity to study the relevance of particular genetic alterations to chemosensitivity and survival. We therefore analyzed these three genes in 72 anaplastic oligodendrogliomas. Deletion mapping demonstrated 10q loss in 14 of 67 informative cases, with the PTEN and DMBT1 regions involved in all deletions but with the ERCC6 locus spared in two cases. Seven tumors had PTEN gene alterations; two had homozygous DMBT1 deletions, but at least one reflected unmasking of a germline DMBT1 deletion. No mutations were found in ERCC6 exon 2. Chemotherapeutic response occurred in two of the seven tumors with PTEN alterations, but with unexpected short survival times. PTEN gene alterations were not associated with poor therapeutic response in multivariate analysis, but were independently predictive of poor prognosis even after multivariate adjustment for both 10q and 1p loss. In anaplastic oligodendroglioma, therefore, PTEN is a target of 10q loss, and PTEN alterations are associated with poor prognosis, even in chemosensitive cases.

Publisher Correction : Probing tumor microenvironment in patients with newly diagnosed glioblastoma during chemoradiation and adjuvant temozolomide with functional MRI (Scientific Reports, (2018), 8, 1, (17062), 10.1038/s41598-018-34820-x)

Ly, K. I., Vakulenko-Lagun, B., Emblem, K. E., Ou, Y., Da, X., Betensky, R., Kalpathy-Cramer, J., Duda, D. G., Jain, R. K., Chi, A. S., Plotkin, S. R., Batchelor, T. T., Sorensen, G., Rosen, B. R., & Gerstner, E. R. (n.d.).

Publication year

2019

Journal title

Scientific reports

Volume

9

Issue

1

10.1038/s41598-019-44365-2

Abstract

Abstract

In the original version of this Article, the author K. Ina Ly was incorrectly indexed. This error has now been corrected.

rBPI21 (opebacan) promotes rapid trilineage hematopoietic recovery in a murine model of high-dose total body irradiation

Janec, K. J., Yuan, H., Norton, J. E., Kelner, R. H., Hirt, C. K., Betensky, R., & Guinan, E. C. (n.d.).

Publication year

2018

Journal title

American Journal of Hematology

Volume

93

Issue

8

Page(s)

1002-1013

10.1002/ajh.25136

Abstract

Abstract

The complexity of providing adequate care after radiation exposure has drawn increasing attention. While most therapeutic development has focused on improving survival at lethal radiation doses, acute hematopoietic syndrome (AHS) occurs at substantially lower exposures. Thus, it is likely that a large proportion of such a radiation-exposed population will manifest AHS of variable degree and that the medical and socioeconomic costs of AHS will accrue. Here, we examined the potential of rBPI21 (opebacan), used without supportive care, to accelerate hematopoietic recovery after radiation where expected survival was substantial (42%-75%) at 30 days. rBPI21 administration was associated with accelerated recovery of hematopoietic precursors and normal marrow cellularity, with increases in megakaryocyte numbers particularly marked. This translated into attaining normal trilineage peripheral blood counts 2-3 weeks earlier than controls. Elevations of hematopoietic growth factors observed in plasma and the marrow microenvironment suggest the mechanism is likely multifactorial and not confined to known endotoxin-neutralizing and cytokine downmodulating activities of rBPI21. These observations deserve further exploration in radiation models and other settings where inadequate hematopoiesis is a prominent feature. These experiments also model the potential of therapeutics to limit the allocation of scarce resources after catastrophic exposures as an endpoint independent of lethality mitigation.

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.

Reader response : Systematic review and statistical analysis of the integrity of 33 randomized controlled trials

Betensky, R., & Chiou, S. H. (n.d.).

Publication year

2018

Journal title

Neurology

Volume

90

Issue

12

Page(s)

578

10.1212/WNL.0000000000005157

Abstract

Abstract

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Recognizing the problem of delayed entry in time-to-event studies : Better late than never for clinical neuroscientists

Betensky, R., & Mandel, M. (n.d.).

Publication year

2015

Journal title

Annals of Neurology

Volume

78

Issue

6

Page(s)

839-844

10.1002/ana.24538

Abstract

Abstract

Editor's Note One of the greatest differences I encountered in moving from being Editor-in-Chief of a basic science journal to the same position at Annals of Neurology was the much greater importance of meticulous review of the statistical treatment of data. In basic science, the conditions of an experiment can be set up by the investigator so that relatively simple statistical treatments can often be used with clear-cut results. Comparing the treatment and outcomes of human studies is much messier. Humans have a history before the study started; they have lives that often cause them to deviate from the protocol; and it is much harder to measure the outcomes because our methods have to be so much less invasive than they can be in animal studies. In addition, unlike mice or rats, which are deliberately inbred in a laboratory to minimize variation between animals, we are a wild species with enormous genetic and environmental variability. We solved the problem of the lack of statistical sophistication of the scientific editors by bringing in an expert in study design and statistical analysis, Dr Rebecca Betensky, a Professor of Biostatistics at the Harvard T. H. Chan School of Public Health, who serves as our Statistical Editor. We have weekly editorial conferences where the Associate Editors, Rebecca, and I consider which of the papers that were reviewed in the previous week should be published. Each week, it seems, we are treated to a private tutorial (sometimes more than one) on the complexities of study design and statistical analysis in the papers we are considering. I have learned a great deal at these meetings and thought that this education should be extended to our readers, and so I have prevailed upon Dr Betensky to address some recurring topics in our editorial conferences. We begin this month with the concept of delayed entry, a common problem in human studies that many investigators and reviewers fail to take into account. We have decided to publish this series under the NeuroGenesis section of the Annals, because this section is devoted to the career development of neurologists, and it seems critical to the professional judgment of every academic neurologist to assimilate the concepts in this series, both to improve our own work and to evaluate the work of other neurologists more critically. - C.B.S.

Redistribution algorithms for censored data

Betensky, R. (n.d.).

Publication year

2000

Journal title

Statistics and Probability Letters

Volume

46

Issue

4

Page(s)

385-389

10.1016/S0167-7152(99)00127-3

Abstract

Abstract

Efron (Proceedings of the Fifth Berkeley Symposium, Vol. 4, University of California Press, Berkeley, CA, pp. 831-853) and Dinse (Amer. Statist. 39, 1985, 299-300) proposed redistribution of mass algorithms for survivor function estimation from right censored data. Dinse's algorithm is easily extended to survivor function estimation from interval censored data and is further extended to incorporate information on disease markers.

Reducing available soluble β-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice

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

Publication year

2012

Journal title

Journal of Neuropathology and Experimental Neurology

Volume

71

Issue

11

Page(s)

1009-1017

10.1097/NEN.0b013e3182729845

Abstract

Abstract

Cerebral amyloid angiopathy (CAA), the accumulation of βamyloid (Aβ) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment and is commonly associated with Alzheimer disease. The progression of CAA, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of Aβ deposition in and clearance from vascular walls and their relationship to the concentration of Aβ in the brain are poorly understood. We manipulated AA levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding "peripheral sink" protein gelsolin and direct inhibition of its formation via administration of LY-411575, a smallmolecule γ-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58% ± 0.15% and 0.52% ± 0.09% to 0.11% T 0.18% (p = 0.04) and j0.17% ± 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. The progression of CAA was also halted when gelsolin was combined with LY-411575 (j0.004% ± 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble Aβ but without evidence of substantial amyloid clearance from vessels.

Reductions in red blood cell 2,3-diphosphoglycerate concentration during continuous renal replacment therapy

Sharma, S., Brugnara, C., Betensky, R., & Waikar, S. S. (n.d.).

Publication year

2015

Journal title

Clinical Journal of the American Society of Nephrology

Volume

10

Issue

1

Page(s)

74-79

10.2215/CJN.02160214

Abstract

Abstract

Background and objectivesHypophosphatemia is a frequent complication during continuous renal replacement therapy (CRRT), a dialytic technique used to treat AKI in critically ill patients. This study sought to confirm that phosphate depletion during CRRT may decrease red blood cell (RBC) concentration of 2,3-diphosphoglycerate (2,3-DPG), a crucial allosteric effector of hemoglobin’s (Hgb’s) affinity for oxygen, thereby leading to impaired oxygen delivery to peripheral tissuesDesign, setting, participants, & measurementsPhosphate mass balance studies were performed in 20 patients with severe AKI through collection of CRRT effluent. RBC concentrations of 2,3-DPG, venous blood gas pH, and oxygen partial pressure required for 50% hemoglobin saturation (P50) were measured at CRRT initiation and days 2, 4, and 7. Similar measurements were obtained on days 0 and 2 in a reference group of 10 postsurgical patients, most of whom did not have AKI. Associations of 2,3-DPG with laboratory parameters and clinical outcomes were examined using mixed-effects and Cox regression modelsResultsMean 2,3-DPG levels decreased from a mean (±SD) of 13.4±3.4µmol/g Hgb to 11.0±3.1µmol/g Hgb after 2 days of CRRT (P