Rebecca A Betensky
Rebecca Betensky
Scroll
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, MAPhD, Statistics, Stanford University, Stanford, CA
-
Areas of research and study
-
BiologyBiostatisticsNeuroepidemiologyNeurologyNeurostatisticsTranslational science
-
Publications
Publications
Maternal dementia age at onset in relation to amyloid burden in non-demented elderly offspring
AbstractMaye, J. E., Betensky, R., Gidicsin, C. M., Locascio, J., Becker, J. A., Pepin, L., Carmasin, J., Rentz, D. M., Marshall, G. A., Blacker, D., Sperling, R. A., & Johnson, K. A. (n.d.).Publication year
2016Journal title
Neurobiology of AgingVolume
40Page(s)
61-67AbstractFamily history (FH) of dementia is a major risk factor for Alzheimer's disease, particularly when the FH is maternal and when the age of dementia onset (AO) is younger. This study tested whether brain amyloid-beta deposition, measured in vivo with 11C-Pittsburgh compound B (PiB), was associated with parental dementia and/or younger parental AO. Detailed FH and positron emission tomography (PiB) data were acquired in 147 nondemented aging individuals (mean age 75 ± 8). No participant had both positive maternal and paternal FH. A series of analyses revealed that those with maternal, but not paternal, FH had greater levels of PiB retention in a global cortical region than those without FH. PiB retention in maternal FH was not significantly greater than paternal FH. Younger maternal dementia AO was related to greater PiB retention in offspring, whereas younger paternal dementia AO was not. Overall, results suggest that not only is amyloid-beta burden greater in individuals with maternal FH, but also that the burden is greater in association with younger maternal AO.Multiple imputation of a randomly censored covariate improves logistic regression analysis
AbstractAtem, F. D., Qian, J., Maye, J. E., Johnson, K. A., & Betensky, R. (n.d.).Publication year
2016Journal title
Journal of Applied StatisticsVolume
43Issue
15Page(s)
2886-2896AbstractRandomly censored covariates arise frequently in epidemiologic studies. The most commonly used methods, including complete case and single imputation or substitution, suffer from inefficiency and bias. They make strong parametric assumptions or they consider limit of detection censoring only. We employ multiple imputation, in conjunction with semi-parametric modeling of the censored covariate, to overcome these shortcomings and to facilitate robust estimation. We develop a multiple imputation approach for randomly censored covariates within the framework of a logistic regression model. We use the non-parametric estimate of the covariate distribution or the semi-parametric Cox model estimate in the presence of additional covariates in the model. We evaluate this procedure in simulations, and compare its operating characteristics to those from the complete case analysis and a survival regression approach. We apply the procedures to an Alzheimer's study of the association between amyloid positivity and maternal age of onset of dementia. Multiple imputation achieves lower standard errors and higher power than the complete case approach under heavy and moderate censoring and is comparable under light censoring. The survival regression approach achieves the highest power among all procedures, but does not produce interpretable estimates of association. Multiple imputation offers a favorable alternative to complete case analysis and ad hoc substitution methods in the presence of randomly censored covariates within the framework of logistic regression.Optimization of Signal Decomposition Matched Filtering (SDMF) for Improved Detection of Copy-Number Variations
AbstractStamoulis, C., & Betensky, R. (n.d.).Publication year
2016Journal title
IEEE/ACM Transactions on Computational Biology and BioinformaticsVolume
13Issue
3Page(s)
584-591AbstractWe aim to improve the performance of the previously proposed signal decomposition matched filtering (SDMF) method [26] for the detection of copy-number variations (CNV) in the human genome. Through simulations, we show that the modified SDMF is robust even at high noise levels and outperforms the original SDMF method, which indirectly depends on CNV frequency. Simulations are also used to develop a systematic approach for selecting relevant parameter thresholds in order to optimize sensitivity, specificity and computational efficiency. We apply the modified method to array CGH data from normal samples in the cancer genome atlas (TCGA) and compare detected CNVs to those estimated using circular binary segmentation (CBS) [19] , a hidden Markov model (HMM)-based approach [11] and a subset of CNVs in the Database of Genomic Variants. We show that a substantial number of previously identified CNVs are detected by the optimized SDMF, which also outperforms the other two methods.Plaque-associated local toxicity increases over the clinical course of Alzheimer disease
AbstractSerrano-Pozo, A., Betensky, R., Frosch, M. P., & Hyman, B. T. (n.d.).Publication year
2016Journal title
American Journal of PathologyVolume
186Issue
2Page(s)
375-384AbstractAmyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312+ dystrophic neurites, GFAP+ reactive astrocytes, and IBA1+ and CD68+ activated microglia in randomly selected dense-core (Thioflavin-S+) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques. Dystrophic neurites (Kendall τ = 0.34, P = 0.001), reactive astrocytes (Kendall τ = 0.30, P = 0.003), and CD68+ (Kendall τ = 0.48, P < 0.0001), but not IBA1 microglia (Kendall τ = 0.045, P = 0.655), exhibited a significant positive correlation with symptom duration. When excluding control subjects, only the positive association between CD68+ microglia and symptom duration remained significant (Kendall τ = 0.39, P = 0.0003). The presence of the APOEε4 allele did not affect these results. We conclude that plaques exert an increasing toxicity in the surrounding neuropil over the clinical course of AD, thereby potentially contributing to cognitive decline.Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV
AbstractGrishchuk, Y., Stember, K. G., Matsunaga, A., Olivares, A. M., Cruz, N. M., King, V. E., Humphrey, D. M., Wang, S. L., Muzikansky, A., Betensky, R., Thoreson, W. B., Haider, N., & Slaugenhaupt, S. A. (n.d.).Publication year
2016Journal title
American Journal of PathologyVolume
186Issue
1Page(s)
199-209AbstractMucolipidosis IV is a debilitating developmental lysosomal storage disorder characterized by severe neuromotor retardation and progressive loss of vision, leading to blindness by the second decade of life. Mucolipidosis IV is caused by loss-of-function mutations in the MCOLN1 gene, which encodes the transient receptor potential channel protein mucolipin-1. Ophthalmic pathology in patients includes corneal haze and progressive retinal and optic nerve atrophy. Herein, we report ocular pathology in Mcoln1-/- mouse, a good phenotypic model of the disease. Early, but non-progressive, thinning of the photoreceptor layer, reduced levels of rhodopsin, disrupted rod outer segments, and widespread accumulation of the typical storage inclusion bodies were the major histological findings in the Mcoln1-/- retina. Electroretinograms showed significantly decreased functional response (scotopic a- and b-wave amplitudes) in the Mcoln1-/- mice. At the ultrastructural level, we observed formation of axonal spheroids and decreased density of axons in the optic nerve of the aged (6-month-old) Mcoln1-/- mice, which indicates progressive axonal degeneration. Our data suggest that mucolipin-1 plays a role in postnatal development of photoreceptors and provides a set of outcome measures that can be used for ocular therapy development for mucolipidosis IV.Tau positron emission tomographic imaging in aging and early Alzheimer disease
AbstractJohnson, K. A., Schultz, A., Betensky, R., Becker, J. A., Sepulcre, J., Rentz, D., Mormino, E., Chhatwal, J., Amariglio, R., Papp, K., Marshall, G., Albers, M., Mauro, S., Pepin, L., Alverio, J., Judge, K., Philiossaint, M., Shoup, T., Yokell, D., … Sperling, R. (n.d.).Publication year
2016Journal title
Annals of NeurologyVolume
79Issue
1Page(s)
110-119AbstractObjective Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease-modifying therapies. Methods We acquired tau positron emission tomography (PET) using 18F T807 (AV1451), and amyloid-β PET using 11C Pittsburgh compound B (PiB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia. Results We found abnormally high cortical 18F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical 18F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal 18F T807 than with mean cortical 11C PIB. Regional 18F T807 was correlated with mean cortical 11C PiB among both impaired and control subjects. Interpretation These findings suggest that 18F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment.Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease continuum
AbstractSerrano-Pozo, A., Qian, J., Muzikansky, A., Monsell, S. E., Montine, T. J., Frosch, M. P., Betensky, R., & Hyman, B. T. (n.d.).Publication year
2016Journal title
Journal of Neuropathology and Experimental NeurologyVolume
75Issue
6Page(s)
516-526AbstractThe 2012 neuropathological criteria for the diagnosis of Alzheimer disease (AD) summarize the extent of AD neuropathological change with an ABC score, which is a composite of the Thal stage of amyloid deposition (A), the Braak stage of neurofibrillary tangles (NFTs) (B), and the CERAD neuritic plaque score (C). NFTs and neuritic plaques are well-established contributors to cognitive impairment, but whether the Thal amyloid stage independently predicts antemortem cognition remains unknown. We used the National Alzheimer's Coordinating Center autopsy data set to build adjacent-categories logit regression models with CDR-SOB and Mini-Mental State Examination (MMSE) scores as cognitive outcome variables. Increasing CERAD scores were independently associated with higher CDR-SOB scores, whereas increasing Braak NFT stages predicted both higher CDR-SOB and lower MMSE scores. Increasing Thal amyloid stages were not significantly independently associated with either outcome measure. Increasing ABC scores predicted higher CDR-SOB and lower MMSE scores. These results raise the possibility that Thal amyloid stages do not substantially contribute to predicting antemortem cognition compared to CERAD neuritic plaque scores and Braak NFT stages, and suggest that the diffuse amyloid deposits participating in the assignment of Thal amyloid stages are neutral with respect to clinically detectable cognitive and functional changes.Thioesterase superfamily member 1 suppresses cold thermogenesis by limiting the oxidation of lipid droplet-derived fatty acids in brown adipose tissue
AbstractOkada, K., LeClair, K. B., Zhang, Y., Li, Y., Ozdemir, C., Krisko, T. I., Hagen, S. J., Betensky, R., Banks, A. S., & Cohen, D. E. (n.d.).Publication year
2016Journal title
Molecular MetabolismVolume
5Issue
5Page(s)
340-351AbstractObjective: Non-shivering thermogenesis in brown adipose tissue (BAT) plays a central role in energy homeostasis. Thioesterase superfamily member 1 (Them1), a BAT-enriched long chain fatty acyl-CoA thioesterase, is upregulated by cold and downregulated by warm ambient temperatures. Them1-/- mice exhibit increased energy expenditure and resistance to diet-induced obesity and diabetes, but the mechanistic contribution of Them1 to the regulation of cold thermogenesis remains unknown. Methods: Them1-/- and Them1+/+ mice were subjected to continuous metabolic monitoring to quantify the effects of ambient temperatures ranging from thermoneutrality (30 °C) to cold (4 °C) on energy expenditure, core body temperature, physical activity and food intake. The effects of Them1 expression on O2 consumption rates, thermogenic gene expression and lipolytic protein activation were determined ex vivo in BAT and in primary brown adipocytes. Results: Them1 suppressed thermogenesis in mice even in the setting of ongoing cold exposure. Without affecting thermogenic gene transcription, Them1 reduced O2 consumption rates in both isolated BAT and primary brown adipocytes. This was attributable to decreased mitochondrial oxidation of endogenous but not exogenous fatty acids. Conclusions: These results show that Them1 may act as a break on uncontrolled heat production and limit the extent of energy expenditure. Pharmacologic inhibition of Them1 could provide a targeted strategy for the management of metabolic disorders via activation of brown fat.A Pairwise Naïve Bayes Approach to Bayesian Classification
AbstractAsafu-Adjei, J. K., & Betensky, R. (n.d.).Publication year
2015Journal title
International Journal of Pattern Recognition and Artificial IntelligenceVolume
29Issue
7AbstractDespite the relatively high accuracy of the naïve Bayes (NB) classifier, there may be several instances where it is not optimal, i.e. does not have the same classification performance as the Bayes classifier utilizing the joint distribution of the examined attributes. However, the Bayes classifier can be computationally intractable due to its required knowledge of the joint distribution. Therefore, we introduce a "pairwise naïve" Bayes (PNB) classifier that incorporates all pairwise relationships among the examined attributes, but does not require specification of the joint distribution. In this paper, we first describe the necessary and sufficient conditions under which the PNB classifier is optimal. We then discuss sufficient conditions for which the PNB classifier, and not NB, is optimal for normal attributes. Through simulation and actual studies, we evaluate the performance of our proposed classifier relative to the Bayes and NB classifiers, along with the HNB, AODE, LBR and TAN classifiers, using normal density and empirical estimation methods. Our applications show that the PNB classifier using normal density estimation yields the highest accuracy for data sets containing continuous attributes. We conclude that it offers a useful compromise between the Bayes and NB classifiers.Accuracy of digital versus conventional implant impressions
AbstractLee, S. J., Betensky, R., Gianneschi, G. E., & Gallucci, G. O. (n.d.).Publication year
2015Journal title
Clinical Oral Implants ResearchVolume
26Issue
6Page(s)
715-719AbstractObjective: The accuracy of digital impressions greatly influences their clinical viability in implant restorations. The aim of this study was to compare the accuracy of gypsum models acquired from the conventional implant impression to digitally milled models created from direct digitalization by three-dimensional analysis. Materials and Methods: Thirty gypsum and 30 digitally milled models, impressed directly from a reference model, were prepared. The models and reference model were scanned by a laboratory scanner, and 30 surface tessellation language datasets from each group were imported to an inspection software program. The datasets were aligned to the reference dataset by a repeated best-fit algorithm, and 10 specified contact locations of interest were measured in mean volumetric deviations. The areas were pooled by cusps, fossae, interproximal contacts, horizontal and vertical axes of implant position and angulation. The pooled areas were statistically analysed by comparing each group to the reference model to investigate the mean volumetric deviations accounting for accuracy and standard deviations for precision. Results: Milled models from digital impressions had comparable accuracy to gypsum models from conventional impressions. However, differences in fossae and vertical displacement of the implant position from the gypsum and digitally milled models compared to the reference model exhibited statistical significance (P < 0.001, P = 0.020, respectively). Conclusion: Milled models from digital impression are comparable to gypsum models from conventional impression.APOEε2 is associated with milder clinical and pathological Alzheimer disease
AbstractSerrano-Pozo, A., Qian, J., Monsell, S. E., Betensky, R., & Hyman, B. T. (n.d.).Publication year
2015Journal title
Annals of NeurologyVolume
77Issue
6Page(s)
917-929AbstractObjective The Alzheimer disease (AD) APOE 4 risk allele associates with an earlier age at onset and increased amyloid-β deposition, whereas the protective APOE 2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOE 2 remain uncertain because of its relative rarity. We investigated the effects of APOE 2 and 4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients. Methods We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOE 3/ 3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination). Results Compared to APOE 3/ 3, APOE 2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOE 4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance ( 2 > 3 > 4). Mediation analysis suggests that this is largely explained through effects on pathology. Interpretation Even when adjusted for age at onset, symptom duration, and other demographic variables, APOE 2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOE 3 and 4 alleles, suggesting a relative neuroprotective effect of APOE 2 in AD.Clinical pertinence metric enables hypothesis-independent genome-phenome analysis for neurologic diagnosis
AbstractSegal, M. M., Abdellateef, M., El-Hattab, A. W., Hilbush, B. S., De La Vega, F. M., Tromp, G., Williams, M. S., Betensky, R., & Gleeson, J. (n.d.).Publication year
2015Journal title
Journal of Child NeurologyVolume
30Issue
7Page(s)
881-888AbstractWe describe an "integrated genome-phenome analysis" that combines both genomic sequence data and clinical information for genomic diagnosis. It is novel in that it uses robust diagnostic decision support and combines the clinical differential diagnosis and the genomic variants using a "pertinence" metric. This allows the analysis to be hypothesis-independent, not requiring assumptions about mode of inheritance, number of genes involved, or which clinical findings are most relevant. Using 20 genomic trios with neurologic disease, we find that pertinence scores averaging 99.9% identify the causative variant under conditions in which a genomic trio is analyzed and family-aware variant calling is done. The analysis takes seconds, and pertinence scores can be improved by clinicians adding more findings. The core conclusion is that automated genome-phenome analysis can be accurate, rapid, and efficient. We also conclude that an automated process offers a methodology for quality improvement of many components of genomic analysis.Computationally simple analysis of matched, outcome-based studies of ordinal disease states
AbstractBetensky, R., Szymonifka, J., Lee, E. Q., Nutt, C. L., & Batchelor, T. T. (n.d.).Publication year
2015Journal title
Statistics in MedicineVolume
34Issue
17Page(s)
2514-2527AbstractOutcome-based sampling is an efficient study design for rare conditions, such as glioblastoma. It is often used in conjunction with matching, for increased efficiency and to potentially avoid bias due to confounding. A study was conducted at the Massachusetts General Hospital that involved retrospective sampling of glioblastoma patients with respect to multiple-ordered disease states, as defined by three categories of overall survival time. To analyze such studies, we posit an adjacent categories logit model and exploit its allowance for prospective analysis of a retrospectively sampled study and its advantageous removal of set and level specific nuisance parameters through conditioning on sufficient statistics. This framework allows for any sampling design and is not limited to one level of disease within each set, such as in previous publications. We describe how this ordinal conditional model can be fit using standard conditional logistic regression procedures. We consider an alternative pseudo-likelihood approach that potentially offers robustness under partial model misspecification at the expense of slight loss of efficiency under correct model specification for small sample sizes. We apply our methods to the Massachusetts General Hospital glioblastoma study.Matrix metalloproteinase 9-mediated intracerebral hemorrhage induced by cerebral amyloid angiopathy
AbstractZhao, L., Arbel-Ornath, M., Wang, X., Betensky, R., Greenberg, S. M., Frosch, M. P., & Bacskai, B. J. (n.d.).Publication year
2015Journal title
Neurobiology of AgingVolume
36Issue
11Page(s)
2963-2971AbstractCerebral amyloid angiopathy (CAA), the deposition of amyloid-β in cerebrovascular walls, is the most common cause of lobar hemorrhagic stroke. Previous studies show that cerebrovascular amyloid-β induces expression and activation of matrix metalloproteinase 9 (MMP-9) in cerebral vessels of amyloid precursor protein transgenic mice. Here, we extended these findings and evaluated MMP-9 expression in postmortem brain tissues of human CAA cases. MMP-9 colocalized with CAA, correlated with the severity of the vascular pathology, and was detected in proximity to microbleeds. We characterized a novel assay using longitudinal multiphoton microscopy and a novel tracer to visualize and quantify the magnitude and kinetics of hemorrhages in three dimensions in living mouse brains. We demonstrated that topical application of recombinant MMP-9 resulted in a time- and dose-dependent cerebral hemorrhage. Amyloid precursor protein mice with significant CAA developed more extensive hemorrhages which also appeared sooner after exposure to MMP-9. Our data suggest an important role for MMP-9 in development of hemorrhages in the setting of CAA. Inhibition of MMP-9 may present a preventive strategy for CAA-associated hemorrhage.Measures of follow-up in time-to-event studies : Why provide them and what should they be?
AbstractBetensky, R. (n.d.).Publication year
2015Journal title
Clinical TrialsVolume
12Issue
4Page(s)
403-408AbstractBackground/Aims: There is some consensus among authors of reports of clinical studies that a measure of follow-up time is informative for the interpretation of the Kaplan-Meier estimate of the survivor function of the event time of interest. Previous authors have suggested that length of follow-up is important to report because the findings of a study should be extracted from the time frame in which most of the subjects have had the event or have remained under observation. This time frame is where the Kaplan-Meier estimate is most stable. This concept of stability is relative to the potential maximum information about the event time distribution contained in the sample; it is not relative to the true, population survivor function. A measure of stability is useful for the interpretation of an interim analysis in which an immature survivor function is presented. Our interest in this article lies in characterizing the unobserved, complete follow-up Kaplan-Meier estimate based on the observed, partial follow-up estimate. Our focus is not on characterizing the true event time distribution relative to its estimate. The concept of stability has not been well-defined in the literature, which has led to inconsistency and lack of transparency across trials in their attempts to capture it through a variety of measures of follow-up. Methods: We report the results of a survey of recent literature on cancer clinical trials and summarize whether follow-up is reported and if so, whether it is well-defined. We define commonly used measures of follow-up in clinical studies. Results: We explain how each measure should be assessed to evaluate the stability of the Kaplan-Meier estimate for the event, and we identify relationships among measures. We propose a new measure that better conveys the desired information about the stability of the current Kaplan-Meier estimate relative to one based on complete follow-up. We apply the proposed measure to a meningioma study for illustration. Conclusion: It is useful for reports of clinical studies to supplement Kaplan-Meier estimates with quantitative assessments of the stability of those estimates relative to the potential follow-up of study participants. We justify the use of one commonly used measure, and we propose a new measure that most directly accomplishes this goal.Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma
AbstractTaylor, J. W., Dietrich, J., Gerstner, E. R., Norden, A. D., Rinne, M. L., Cahill, D. P., Stemmer-Rachamimov, A., Wen, P. Y., Betensky, R., Giorgio, D. H., Snodgrass, K., Randall, A. E., Batchelor, T. T., & Chi, A. S. (n.d.).Publication year
2015Journal title
Journal of Neuro-OncologyVolume
121Issue
3Page(s)
557-563AbstractTumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7–9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.Power and sample size calculations for the Wilcoxon-Mann-Whitney test in the presence of death-censored observations
AbstractMatsouaka, R. A., & Betensky, R. (n.d.).Publication year
2015Journal title
Statistics in MedicineVolume
34Issue
3Page(s)
406-431AbstractWe 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.Recognizing the problem of delayed entry in time-to-event studies : Better late than never for clinical neuroscientists
AbstractBetensky, R., & Mandel, M. (n.d.).Publication year
2015Journal title
Annals of NeurologyVolume
78Issue
6Page(s)
839-844AbstractEditor'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.Reductions in red blood cell 2,3-diphosphoglycerate concentration during continuous renal replacment therapy
AbstractSharma, S., Brugnara, C., Betensky, R., & Waikar, S. S. (n.d.).Publication year
2015Journal title
Clinical Journal of the American Society of NephrologyVolume
10Issue
1Page(s)
74-79AbstractBackground 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 (PResearch participant compensation : A matter of statistical inference as well as ethics
AbstractSwanson, D. M., & Betensky, R. (n.d.).Publication year
2015Journal title
Contemporary Clinical TrialsVolume
45Page(s)
265-269AbstractThe ethics of compensation of research subjects for participation in clinical trials has been debated for years. One ethical issue of concern is variation among subjects in the level of compensation for identical treatments. Surprisingly, the impact of variation on the statistical inferences made from trial results has not been examined. We seek to identify how variation in compensation may influence any existing dependent censoring in clinical trials, thereby also influencing inference about the survival curve, hazard ratio, or other measures of treatment efficacy. In simulation studies, we consider a model for how compensation structure may influence the censoring model. Under existing dependent censoring, we estimate survival curves under different compensation structures and observe how these structures induce variability in the estimates. We show through this model that if the compensation structure affects the censoring model and dependent censoring is present, then variation in that structure induces variation in the estimates and affects the accuracy of estimation and inference on treatment efficacy. From the perspectives of both ethics and statistical inference, standardization and transparency in the compensation of participants in clinical trials are warranted.The influence of vascular risk factors and stroke on cognition in late life analysis of the NACC cohort
AbstractViswanathan, A., Macklin, E. A., Betensky, R., Hyman, B., Smith, E. E., & Blacker, D. (n.d.).Publication year
2015Journal title
Alzheimer disease and associated disordersVolume
29Issue
4Page(s)
287-293AbstractObjective: Vascular risk factors in mid-life predict late life cognitive decline in previously normal populations. We sought to investigate the contribution of vascular risk factors in late life to cognitive decline in a cohort of normal elderly individuals. Methods: Cognitively normal subjects were identified from the longitudinal cohort of participants in the National Alzheimer Coordinating Center (NACC) database (n=2975). The association between a composite score of vascular risk factors (based on the Framingham Stroke Risk Profile) and cognitive function was tested at baseline visit and estimated in longitudinal analyses using linear mixed-effects models. Results: Total vascular risk factor burden was associated with worse cognitive performance at baseline and faster decline longitudinally in univariate analyses but only with worse WAIS digit symbol performance in cross-sectional (estimate=-0.266 units/1 unit of Framingham Stroke Risk Profile Score; 95% confidence interval,-0.380 to-0.153; PVandetanib plus sirolimus in adults with recurrent glioblastoma : results of a phase I and dose expansion cohort study
AbstractChheda, M. G., Wen, P. Y., Hochberg, F. H., Chi, A. S., Drappatz, J., Eichler, A. F., Yang, D., Beroukhim, R., Norden, A. D., Gerstner, E. R., Betensky, R., & Batchelor, T. T. (n.d.).Publication year
2015Journal title
Journal of Neuro-OncologyVolume
121Issue
3Page(s)
627-634AbstractTargeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease
AbstractMormino, E. C., Betensky, R., Hedden, T., Schultz, A. P., Ward, A., Huijbers, W., Rentz, D. M., Johnson, K. A., & Sperling, R. A. (n.d.).Publication year
2014Journal title
NeurologyVolume
82Issue
20Page(s)
1760-1767AbstractObjective: To examine whether b-amyloid (Ab) and APOE ε4 status independently contribute or interact to influence longitudinal cognitive decline in clinically normal older individuals (CN). Methods: Data from 490 CNs were aggregated across 3 observational cohort studies (Harvard Aging Brain Study, Alzheimer's Disease Neuroimaging Initiative, and Australian Imaging Biomarkers and Lifestyle Study of Ageing; median age = 75.0 years, 255 female), and the contributions of APOE ε4 and Aβ on longitudinal change over a median of 1.49 years were examined. Cognitive decline was assessed with the Mini-Mental State Examination (MMSE) and Logical Memory (immediate and delayed recall scores). Results: High Aβ participants were more likely to be APOE ε4+ than low Aβ participants. CNs who were both high Aβ and APOE ε4+ showed greater decline in Logical Memory immediate recall (p < 0.087), Logical Memory delayed recall (p < 0.024), and MMSE (p < 0.034) compared to all other groups (low Aβ/APOE ε4-, low Aβ/APOE ε4+, and high Aβ/APOE ε4-). No other pairwise contrast was significant for any cognitive measure. Conclusions: Clinically normal individuals who are APOE ε4+ and have high Aβ showed the highest cognitive decline. These results suggest that Aβ and APOE ε4 are not redundant contributors of decline in aging but rather interact to promote decline during the short follow-up period examined in this study. Longer follow-up periods will be essential to fully elucidate the influence of Alzheimer disease risk factors on cognitive decline in aging.Anatomic pattern of intracerebral hemorrhage expansion : Relation to CT angiography spot sign and hematoma center
AbstractBoulouis, G., Dumas, A., Betensky, R., Brouwers, H. B., Fotiadis, P., Vashkevich, A., Ayres, A., Schwab, K., Romero, J. M., Smith, E. E., Viswanathan, A., Goldstein, J. N., Rosand, J., Gurol, M. E., & Greenberg, S. M. (n.d.).Publication year
2014Journal title
StrokeVolume
45Issue
4Page(s)
1154-1156AbstractBACKGROUND AND PURPOSE - : We sought to identify baseline determinants of the anatomic pattern of hematoma expansion in patients with intracerebral hemorrhage and spot sign. METHODS - : We coregistered baseline and follow-up CT scans from 15 intracerebral hemorrhage patients and measured growth at each surface node from baseline to follow-up hematoma. We analyzed the effects of proximity to the spot sign or hematoma center on distance of expansion, controlling for covariates. RESULTS - : There was substantial node-to-node variation in the extent of expansion around each hematoma surface (mean coefficient of variation for expansion distance, 0.43; 95% confidence interval, 0.39-0.48), indicating nonuniform expansion. Closer proximity to the hematoma center was independently associated with increased expansion (0.185 mm greater expansion for each 1 mm closer to the center; PAnti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis
AbstractLiao, F., Hori, Y., Hudry, E., Bauer, A. Q., Jiang, H., Mahan, T. E., Lefton, K. B., Zhang, T. J., Dearborn, J. T., Kim, J., Culver, J. P., Betensky, R., Wozniak, D. F., Hyman, B. T., & Holtzman, D. M. (n.d.).Publication year
2014Journal title
Journal of NeuroscienceVolume
34Issue
21Page(s)
7281-7292AbstractApolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1 ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology.