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
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.Maximally selected χ2 statistics for k x 2 tables
AbstractBetensky, R., & Rabinowitz, D. (n.d.).Publication year
1999Journal title
BiometricsVolume
55Issue
1Page(s)
317-320AbstractIt is common in epidemiologic analyses to summarize continuous outcomes as falling above or below a threshold. With such a dichotomized outcome, the usual χ2 statistics for association or trend can be used to test for equality of proportions across strata of the study population. However, if the threshold is chosen to maximize the test statistic, the nominal χ2 reference distributions are incorrect. In this paper, the asymptotic distributions of maximally selected χ2 statistics for association and for trend for the k x 2 table are derived. The methodology is illustrated with data from an AIDS clinical trial. The results of simulation experiments that assess the accuracy of the asymptotic distributions in moderate sample sizes are also reported.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.Methods to classify familial relationships in the presence of laboratory errors, without parental data
AbstractZhang, B., & Betensky, R. (n.d.).Publication year
2006Journal title
Human GeneticsVolume
119Issue
6Page(s)
642-648AbstractWe consider the problem of accurate classification of family relationship in the presence of laboratory error without parental data. We first propose an adjusted version of the test statistic proposed by Ehm and Wagner based on the summation over a large number of genetics markers. We then propose use of the Bayes factor as a classification rule. We prove theoretically that the Bayes factor is the optimal classification rule in that the total classification error is minimized. We show via simulations that both the adjusted Ehm and Wagner method and Bayes factor classification rule reduce misclassification errors, and that the Bayes factor classification rule is robust against under-estimation or over-estimation of laboratory errors. For monozygotic twins versus dizygotic twins, the correct classification rate of the Bayes rule is over 99%. For full-siblings versus half-siblings, the Bayes factor classification rule generally outperforms Ehm and Wagner's method (in Am J Hum Genet 62:181-188, 1998, especially when full-sibling proportion is high.Microbleeds versus macrobleeds : Evidence for distinct entities
AbstractGreenberg, S. M., Kaveer Nandigam, R. N., Delgado, P., Betensky, R., 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 (Mild to moderate Alzheimer dementia with insufficient neuropathological changes
AbstractSerrano-Pozo, A., Qian, J., Monsell, S. E., Blacker, D., Gómez-Isla, T., Betensky, R., Growdon, J. H., Johnson, K. A., Frosch, M. P., Sperling, R. A., & Hyman, B. T. (n.d.).Publication year
2014Journal title
Annals of NeurologyVolume
75Issue
4Page(s)
597-601AbstractRecently, ∼16% of participants in an anti-Aβ passive immunotherapy trial for mild-to-moderate Alzheimer disease (AD) had a negative baseline amyloid positron emission tomography (PET) scan. Whether they have AD or are AD clinical phenocopies remains unknown. We examined the 2005-2013 National Alzheimer's Coordinating Center autopsy database and found that ∼14% of autopsied subjects clinically diagnosed with mild-to-moderate probable AD have no or sparse neuritic plaques, which would expectedly yield a negative amyloid PET scan. More than half of these "Aβ-negative" subjects have low neurofibrillary tangle Braak stages. These findings support the implementation of a positive amyloid biomarker as an inclusion criterion in future anti-Aβ drug trials. Ann Neurol 2014;75:597-601Molecular evolution of human adenoviruses
AbstractRobinson, C. M., Singh, G., Lee, J. Y., Dehghan, S., Rajaiya, J., Liu, E. B., Yousuf, M. A., Betensky, R., Jones, M. S., Dyer, D. W., Seto, D., & Chodosh, J. (n.d.).Publication year
2013Journal title
Scientific reportsVolume
3AbstractThe recent emergence of highly virulent human adenoviruses (HAdVs) with new tissue tropisms underscores the need to determine their ontogeny. Here we report complete high quality genome sequences and analyses for all the previously unsequenced HAdV serotypes (n = 20) within HAdV species D. Analysis of nucleotide sequence variability for these in conjunction with another 40 HAdV prototypes, comprising all seven HAdV species, confirmed the uniquely hypervariable regions within species. The mutation rate among HAdV-Ds was low when compared to other HAdV species. Homologous recombination was identified in at least two of five examined hypervariable regions for every virus, suggesting the evolution of HAdV-Ds has been highly dependent on homologous recombination. Patterns of alternating GC and AT rich motifs correlated well with hypervariable region recombination sites across the HAdV-D genomes, suggesting foci of DNA instability lead to formulaic patterns of homologous recombination and confer agility to adenovirus evolution.Molecular subtypes of anaplastic oligodendroglioma : Implications for patient management at diagnosis
AbstractIno, Y., Betensky, R., Zlatescu, M. C., Sasaki, H., Macdonald, D. R., Stemmer-Rachamimov, A. O., Ramsay, D. A., Cairncross, J. G., & Louis, D. N. (n.d.).Publication year
2001Journal title
Clinical Cancer ResearchVolume
7Issue
4Page(s)
839-845AbstractPurpose: In a prior study of anaplastic oligodendrogliomas treated with chemotherapy at diagnosis or at recurrence after radiotherapy, allelic loss of chromosome 1p correlated with better chemotherapeutic response and overall survival. However, in this group of patients in whom therapeutic management was not uniform, loss of 1p did not identify all chemosensitive tumors, nor did all patients whose tumors harbor a 1p loss have long survival. Experimental Design: To clarify the clinical relevance of molecular genetic testing at the time of diagnosis for patients with anaplastic oligodendrogliomas, we studied a larger, more homogeneous group of 50 patients with histologically defined anaplastic oligodendrogliomas treated with a chemotherapeutic regimen as the principal initial therapy. Results: We demonstrate that these tumors can be divided genetically into four therapeutically and prognostically relevant subgroups. Patients whose tumors have combined but isolated losses of 1p and 19q have marked and durable responses to chemotherapy associated with long survival, with or without postoperative radiation therapy. Other tumors with chromosome 1p alterations also respond to chemotherapy, but with shorter duration of response and patient survival. Tumors lacking 1p loss can also be divided into two subgroups: those with TP53 mutations, which may also respond to chemotherapy but recur quickly, and those without TP53 mutations, which are poorly responsive, aggressive tumors that are clinically and genotypically similar to glioblastomas. Conclusions: These data raise the possibility, for the first time, that therapeutic decisions at the time of diagnosis might be tailored to particular genetic subtypes of anaplastic oligodendroglioma.Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma
AbstractSnuderl, M., Fazlollahi, L., Le, L. P., Nitta, M., Zhelyazkova, B. H., Davidson, C. J., Akhavanfard, S., Cahill, D. P., Aldape, K. D., Betensky, R., Louis, D. N., & Iafrate, A. J. (n.d.).Publication year
2011Journal title
Cancer CellVolume
20Issue
6Page(s)
810-817AbstractTumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies.Mucocutaneous Manifestations of Multisystem Inflammatory Syndrome in Children during the COVID-19 Pandemic
AbstractYoung, T. K., Shaw, K. S., Shah, J. K., Noor, A., Alperin, R. A., Ratner, A. J., Orlow, S. J., Betensky, R., Shust, G. F., Kahn, P. J., & Oza, V. S. (n.d.).Publication year
2021Journal title
JAMA DermatologyVolume
157Issue
2Page(s)
207-212AbstractImportance: To date, no study has characterized the mucocutaneous features seen in hospitalized children with multisystem inflammatory syndrome in children (MIS-C) or the temporal association of these findings with the onset of systemic symptoms. Objective: To describe the mucocutaneous findings seen in children with MIS-C during the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City in 2020. Design, Setting, and Participants: A retrospective case series was conducted of 35 children admitted to 2 hospitals in New York City between April 1 and July 14, 2020, who met Centers for Disease Control and Prevention and/or epidemiologic criteria for MIS-C. Main Outcomes and Measures: Laboratory and clinical characteristics, with emphasis on mucocutaneous findings, of children who met criteria for MIS-C. The characterization of mucocutaneous features was verified by 2 board-certified pediatric dermatologists. Results: Twenty-five children (11 girls [44%]; median age, 3 years [range, 0.7-17 years]) were identified who met definitional criteria for MIS-C; an additional 10 children (5 girls [50%]; median age, 1.7 years [range, 0.2-15 years]) were included as probable MIS-C cases (patients met all criteria with the exception of laboratory test evidence of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection or known exposure). The results of polymerase chain reaction tests for SARS-CoV-2 were positive for 10 patients (29%), and the results of SARS-CoV-2 immunoglobulin G tests were positive for 19 patients (54%). Of the 35 patients, 29 (83%) exhibited mucocutaneous changes, with conjunctival injection (n = 21), palmoplantar erythema (n = 18), lip hyperemia (n = 17), periorbital erythema and edema (n = 7), strawberry tongue (n = 8), and malar erythema (n = 6) being the most common findings. Recognition of mucocutaneous findings occurred a mean of 2.7 days (range, 1-7 days) after the onset of fever. The duration of mucocutaneous findings varied from hours to days (median duration, 5 days [range, 0-11 days]). Neither the presence nor absence of mucocutaneous findings was significantly associated with overall disease severity. Conclusions and Relevance: In this case series of hospitalized children with suspected MIS-C during the COVID-19 pandemic, a wide spectrum of mucocutaneous findings was identified. Despite their protean and transient nature, these mucocutaneous features serve as important clues in the recognition of MIS-C.Multicrossover Randomized Controlled Trial Designs in Alzheimer Disease
AbstractArnold, S. E., & Betensky, R. (n.d.).Publication year
2018Journal title
Annals of NeurologyVolume
84Issue
2Page(s)
168-175Abstract~Multiple imputation for early stopping of a complex clinical trial
AbstractBetensky, R. (n.d.).Publication year
1998Journal title
BiometricsVolume
54Issue
1Page(s)
229-242AbstractIt is desirable to have procedures available for stopping a clinical trial early if there appears to be no treatment effect. Conditional power procedures allow for early stopping in favor of the null hypothesis if the probability of rejecting H0 at the planned end of the trial given the current data and a value of the parameter of interest is below some threshold level. Lan, Simon, and Halperin (1982, Communications in Statistics C1, 207- 219) proposed a stochastic curtailment procedure that calculates the conditional power under the alternative hypothesis. Alternatively, predictive power procedures incorporate information from the observed data by averaging the conditional power over the posterior distribution of the parameter. For complex problems in which explicit evaluation of conditional power is not possible, we propose treating the problem of projecting the outcome of a trial given the current data as a missing data problem. We then complete the data using multiple imputation and thus eliminate the need for explicit calculation of conditional power. We apply this method to AIDS Clinical Trials Group (ACTG) protocol 118 and to several simulated clinical trials.Multiple imputation for simple estimation of the hazard function based on interval censored data
AbstractBebchuk, J. D., & Betensky, R. (n.d.).Publication year
2000Journal title
Statistics in MedicineVolume
19Issue
3Page(s)
405-419AbstractA data augmentation algorithm is presented for estimating the hazard function and pointwise variability intervals based on interval censored data. The algorithm extends that proposed by Tanner and Wong for grouped right censored data to interval censored data. It applies multiple imputation and local likelihood methods to obtain smooth non-parametric estimates for the hazard function. This approach considerably simplifies the problem of estimation for interval censored data as it transforms it into the more tractable problem of estimation for right censored data. The method is illustrated for two real data sets: times to breast cosmesis deterioration and times to HIV-1 infection for individuals with haemophilia. Simulations are presented to assess the effects of various parameters on the estimates and their variances. Copyright (C) 2000 John Wiley and Sons, Ltd.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.Multivariate logistic regression for familial aggregation in age at disease onset
AbstractMatthews, A. G., Finkelstein, D. M., & Betensky, R. (n.d.).Publication year
2007Journal title
Lifetime Data AnalysisVolume
13Issue
2Page(s)
191-209AbstractFamilial aggregation studies seek to identify diseases that cluster in families. These studies are often carried out as a first step in the search for hereditary factors affecting the risk of disease. It is necessary to account for age at disease onset to avoid potential misclassification of family members who are disease-free at the time of study participation or who die before developing disease. This is especially true for late-onset diseases, such as prostate cancer or Alzheimer's disease. We propose a discrete time model that accounts for the age at disease onset and allows the familial association to vary with age and to be modified by covariates, such as pedigree relationship. The parameters of the model have interpretations as conditional log-odds and log-odds ratios, which can be viewed as discrete time conditional cross hazard ratios. These interpretations are appealing for cancer risk assessment. Properties of this model are explored in simulation studies, and the method is applied to a large family study of cancer conducted by the National Cancer Institute-sponsored Cancer Genetics Network (CGN).Multivariate logistic regression for familial aggregation of two disorders. I. Development of models and methods
AbstractHudson, J. I., Laird, N. M., & Betensky, R. (n.d.).Publication year
2001Journal title
American Journal of EpidemiologyVolume
153Issue
5Page(s)
500-505AbstractThe question of whether two disorders cluster together, or coaggregate, within families often arises. This paper considers how to analyze familial aggregation of two disorders and presents two multivariate logistic regression methods that model both disorder outcomes simultaneously. The first, a proband predictive model, predicts a relative's outcomes (the presence or absence of each of the two disorders) by using the proband's disorder status. The second, a family predictive model derived from the quadratic exponential model, predicts a family member's outcomes by using all of the remaining family members' disorder statuses. The models are more realistic, flexible, and powerful than univariate models. Methods for estimation and testing account for the correlation of outcomes among family members and can be implemented by using commercial software.Multivariate logistic regression for familial aggregation of two disorders. II. Analysis of studies of eating and mood disorders
AbstractHudson, J. I., Laird, N. M., Betensky, R., Keck, P. E., & Pope, H. G. (n.d.).Publication year
2001Journal title
American Journal of EpidemiologyVolume
153Issue
5Page(s)
506-514AbstractFamily studies have suggested that eating disorders and mood disorders may coaggregate within families. Previous studies, however, have been limited by use of univariate modeling techniques and failure to account for the correlation of observations within families. To provide a more efficient analysis and to illustrate multivariate logistic regression models for familial aggregation of two disorders, the authors analyzed pooled data from two previously published family studies (conducted in Massachusetts in 1984-1986 and 1986-1987) by using multivariate proband predictive and family predictive models. Both models demonstrated a significant familial aggregation of mood disorders and familial coaggregation of eating and mood disorders. The magnitude of the coaggregation between eating and mood disorders was similar to that of the aggregation of mood disorders. Similar results were obtained with alternative models, including a traditional univariate proband predictive model. In comparison with the univariate model, the multivariate models provided greater flexibility, improved precision, and wider generality for interpreting aggregation effects.Neurofibrillary tangle stage and the rate of progression of Alzheimer symptoms : Modeling using an autopsy cohort and application to clinical trial design
AbstractQian, J., Hyman, B. T., & Betensky, R. (n.d.).Publication year
2017Journal title
JAMA NeurologyVolume
74Issue
5Page(s)
540-548AbstractIMPORTANCE The heterogeneity of rate of clinical progression among patients with Alzheimer disease leads to difficulty in providing clinical counseling and diminishes the power of clinical trials using disease-modifying agents. OBJECTIVE To gain a better understanding of the factors that affect the natural history of progression in Alzheimer disease for the purpose of improving both clinical care and clinical trial design. DESIGN, SETTING, AND PARTICIPANTS A longitudinal cohort study of aging from 2005 to 2014 in the National Alzheimer Coordinating Center. Clinical evaluation of the participants was conducted in 31 National Institute on Aging's Alzheimer Disease Centers. Nine hundred eighty-four participants in the National Alzheimer Coordinating Center cohort study who died and underwent autopsy and met inclusion and exclusion criteria. MAIN OUTCOMES AND MEASURES We sought to model the possibility that knowledge of neurofibrillary tangle burden in the presence of moderate or frequent plaques would add to the ability to predict clinical rate of progression during the ensuing 2 to 3 years.We examined the National Alzheimer Coordinating Center autopsy data to evaluate the effect of different neurofibrillary tangle stages on the rates of progression on several standard clinical instruments: the Clinical Dementia Rating Scale sum of boxes, a verbal memory test (logical memory), and a controlled oral word association task (vegetable naming), implementing a reverse-time longitudinal modeling approach in conjunction with latent class estimation to adjust for unmeasured sources of heterogeneity. RESULTS Several correlations between clinical variables and neurocognitive performance suggest a basis for heterogeneity: Higher education level was associated with lower Clinical Dementia Rating Scale sum of boxes (β = -0.19; P < .001), and frequent vs moderate neuritic plaques were associated with higher Clinical Dementia Rating Scale sum of boxes (β = 1.64; P < .001) and lower logical memory score (β = -1.07; P = .005). The rate of change of the clinical and cognitive scores varied depending on Braak stage, when adjusting for plaques, age of death, sex, education, and APOE genotype. For example, comparing high vs low Braak stage with other variables fixed, the logical memory score decreased a substantial 0.38 additional units per year (95%CI, -0.70 to -0.06; P = .02). Using these data, we estimate that a 300-participant clinical trial with end point of a 20% improvement in slope in rate of change of Clinical Dementia Rating Scale sum of boxes has 89%power when all participants in the trial are from the high Braak stage, compared with 29% power if Braak stage had not used for eligibility. CONCLUSIONS AND RELEVANCE We found that knowledge of neurofibrillary tangle stage, modeled as the sort of information that could be available from tau positron-emission tomography scans and its use to determine eligibility to a trial, could dramatically improve the power of clinical trials and equivalently reduce the required sample sizes of clinical trials.Neurolymphomatosis
AbstractBaehring, J. M., Damek, D., Martin, E. C., Betensky, R., & Hochberg, F. H. (n.d.).Publication year
2003Journal title
Neuro-OncologyVolume
5Issue
2Page(s)
104-115AbstractThe term "neurolymphomatosis" (NL) has included infiltration of the peripheral nervous system by lymphoma and nontumor lymphocytes. We describe NL as a lymphoma entity that affects cranial and peripheral nerves and roots. We reviewed the medical records of patients at the Massachusetts General Hospital (MGH) who registered between 1972 and 2000, as well as cases published in the English-language literature. Inclusion criteria were (A) histopathologic demonstration of lymphoma within peripheral nerve, nerve root/plexus, or cranial nerve or (B) CT/MRI or intraoperative evidence of nerve enlargement and/or enhancement beyond the dural sleeve in the setting of prior or concurrent lymphoma in systemic or CNS sites. We identified 25 patients with NL in addition to 47 reported by others. Four clinical presentations were (1) painful involvement of nerves or roots, (2) cranial neuropathy with or without pain, (3) painless involvement of peripheral nerves, (4) painful or painless involvement of a single peripheral nerve. Twenty of our patients and 44 of those reported had histopathologic confirmation of lymphoma infiltrating root or nerve. In the remainder, diagnosis was based upon clinical presentation, nodular nerve enlargement or enhancement, and lymphoma cells in spinal fluid or extraneural sites. For antemortem diagnosis, imaging studies were of greatest utility, followed by biopsy. Thirty-three patients of the combined series were not correctly diagnosed until postmortem examination. Systemic chemotherapy was used to address the multiple potential sites of involvement. When properly treated, NL carries a prognosis similar to primary CNS lymphoma in the modern era.Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain
AbstractHopp, S. C., Bihlmeyer, N. A., Corradi, J. P., Vanderburg, C., Cacace, A. M., Das, S., Clark, T. W., Betensky, R., Hyman, B. T., & Hudry, E. (n.d.).Publication year
2018Journal title
Journal of NeurochemistryVolume
147Issue
1Page(s)
24-39AbstractSynaptic dysfunction and loss are core pathological features in Alzheimer disease (AD). In the vicinity of amyloid-β plaques in animal models, synaptic toxicity occurs and is associated with chronic activation of the phosphatase calcineurin (CN). Indeed, pharmacological inhibition of CN blocks amyloid-β synaptotoxicity. We therefore hypothesized that CN-mediated transcriptional changes may contribute to AD neuropathology and tested this by examining the impact of CN over-expression on neuronal gene expression in vivo. We found dramatic transcriptional down-regulation, especially of synaptic mRNAs, in neurons chronically exposed to CN activation. Importantly, the transcriptional profile parallels the changes in human AD tissue. Bioinformatics analyses suggest that both nuclear factor of activated T cells and numerous microRNAs may all be impacted by CN, and parallel findings are observed in AD. These data and analyses support the hypothesis that at least part of the synaptic failure characterizing AD may result from aberrant CN activation leading to down-regulation of synaptic genes, potentially via activation of specific transcription factors and expression of repressive microRNAs. Open Practices: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/. (Figure presented.). Read the Editorial Highlight for this article on page 8.Neuropathology-Independent Association Between Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum
AbstractBetensky, R., Qian, J., Zhang, Y., Betensky, R. A., Hyman, B. T., & Serrano-Pozo, A. (n.d.).Publication year
2023Journal title
Neurology. GeneticsVolume
9Issue
1Page(s)
e200055AbstractWe previously found that the genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies.Neuropathology-Independent Association between APOE Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum
AbstractQian, J., Zhang, Y., Betensky, R., Hyman, B. T., & Serrano-Pozo, A. (n.d.).Publication year
2023Journal title
Neurology: GeneticsVolume
9Issue
1AbstractBackground and ObjectivesWe previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies.MethodsWe analyzed APOE associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling.ResultsCarrying the APOEϵ4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to APOEϵ3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which APOEϵ4 carriers declined faster than APOEϵ3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in APOEϵ4 vs APOEϵ3/ϵ3; MMSE: 88.6% of individuals, -0.303 vs -0.153 points/y in APOEϵ4 vs APOEϵ3/ϵ3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in APOEϵ4 vs APOEϵ3/ϵ3; MMSE: 11.4% of participants, -2.538 vs -2.387 points/y in APOEϵ4 vs APOEϵ3/ϵ3). Compared with slow decliners, fast decliners were more likely to carry the APOEϵ4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy.DiscussionIn a large national sample selected to represent the normal aging-early AD continuum, the APOEϵ4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies.New guidelines for statistical reporting
AbstractBetensky, R., & Newberger, N. G. (n.d.).Publication year
2019Journal title
New England Journal of MedicineVolume
381Issue
16Page(s)
1597Abstract~No, it's not 1976 all over again
AbstractRutkove, S. B., & Betensky, R. (n.d.).Publication year
2021Journal title
Annals of NeurologyVolume
90Issue
2Page(s)
189-190Abstract~Nonidentifiability in the presence of factorization for truncated data
AbstractBetensky, R., Vakulenko-Lagun, B., Qian, J., Chiou, S. H., & Betensky, R. A. (n.d.).Publication year
2019Journal title
BiometrikaVolume
106Issue
3Page(s)
724-731AbstractA time to event, X , is left-truncated by T if X can be observed only if T < X . This often results in oversampling of large values of X , and necessitates adjustment of estimation procedures to avoid bias. Simple risk-set adjustments can be made to standard risk-set-based estimators to accommodate left truncation when T and X are quasi-independent. We derive a weaker factorization condition for the conditional distribution of T given X in the observable region that permits risk-set adjustment for estimation of the distribution of X , but not of the distribution of T. Quasi-independence results when the analogous factorization condition for X given T holds also, in which case the distributions of X and T are easily estimated. While we can test for factorization, if the test does not reject, we cannot identify which factorization condition holds, or whether quasi-independence holds. Hence we require an unverifiable assumption in order to estimate the distribution of X or T based on truncated data. This contrasts with the common understanding that truncation is different from censoring in requiring no unverifiable assumptions for estimation.We illustrate these concepts through a simulation of left-truncated and right-censored data.