Rebecca A Betensky
Rebecca Betensky
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Chair of the Department of Biostatistics
Professor of Biostatistics
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Professional overview
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Prior to NYU, Dr. Betensky was Professor of Biostatistics at the Harvard T.H. Chan School of Public Health. She was director of the Harvard Catalyst (Clinical and Translational Science Award) Biostatistics Program; director of the Data and Statistics Core for the Massachusetts Alzheimer’s Disease Research Center; and director of the Biostatistics Neurology Core at Massachusetts General Hospital. Previously, she was the Biostatistics Program Leader for the Dana-Farber/Harvard Cancer Center.
Dr. Betensky’s research focuses on methods for the analysis of censored and truncated outcomes and covariates, which frequently arise from the subsampling of cohort studies. She has a long-time interest in clinical trials, and has written on the evaluation of biomarkers and the use and interpretation of p-values. She has collaborated extensively in studies in neurologic diseases, and serves as statistical editor for Annals of Neurology.
Dr. Betensky was awarded, and directed for 15 years, an NIH T32 training program in neurostatistics and neuroepidemiology for pre- and post-doctoral students in biostatistics and epidemiology and for clinician-scientists. She previously directed Harvard’s Biostatistics programs to promote and support diversity at all levels in the field of quantitative public health. She was also a member of the BMRD Study Section for review of NIH statistical methodology grants; on committees for the Institute of Medicine; and a co-chair of the technical advisory committee for the scientific registry of transplant recipients.
Dr. Betensky an elected Fellow of the American Statistical Association and of the International Statistical Institute, and is a past recipient of the Spiegelman Award from the American Public Health Association. She currently serves as a member of the Board of Scientific Counselors for Clinical Science and Epidemiology at the National Cancer Institute.
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Education
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AB, Mathematics, Harvard University, Cambridge, MAPhD, Statistics, Stanford University, Stanford, CA
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Areas of research and study
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BiologyBiostatisticsNeuroepidemiologyNeurologyNeurostatisticsTranslational science
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Publications
Publications
Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals
AbstractMormino, E. C., Betensky, R., Hedden, T., Schultz, A. P., Amariglio, R. E., Rentz, D. M., Johnson, K. A., & Sperling, R. A. (n.d.).Publication year
2014Journal title
JAMA NeurologyVolume
71Issue
11Page(s)
1379-1385AbstractIMPORTANCE: Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes. OBJECTIVE: To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals. DESIGN, SETTING, AND PARTICIPANTS: Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women). MAIN OUTCOMES AND MEASURES: The Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ+/ND-), stage 2 (Aβ+/ND+), and suspected non-Alzheimer disease pathology (Aβ-/ND+). Cognition was assessed with a composite of neuropsychological tests administered annually. RESULTS: The Aβ+ CN individuals were more likely to be classified as ND+: 59.6%of Aβ+ CN individuals were ND+, whereas 31.9%of Aβ- CN individuals were ND+ (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04). CONCLUSIONS AND RELEVANCE: The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy
AbstractKopeikina, K. J., Wegmann, S., Pitstick, R., Carlson, G. A., Bacskai, B. J., Betensky, R., Hyman, B. T., & Spires-Jones, T. L. (n.d.).Publication year
2013Journal title
PloS oneVolume
8Issue
11AbstractNeurofibrillary tangles (NFTs) of tau are one of the defining hallmarks of Alzheimer's disease (AD), and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease
AbstractBennett, R. E., Robbins, A. B., Hu, M., Cao, X., Betensky, R., Clark, T., Das, S., & Hyman, B. T. (n.d.).Publication year
2018Journal title
Proceedings of the National Academy of Sciences of the United States of AmericaVolume
115Issue
6Page(s)
E1289-E1298AbstractMixed pathology, with both Alzheimer's disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer's disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa, Serpine1, and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain's microvasculature.Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses
AbstractRudinskiy, N., Hawkes, J. M., Wegmann, S., Kuchibhotla, K. V., Muzikansky, A., Betensky, R., Spires-Jones, T. L., & Hyman, B. T. (n.d.).Publication year
2014Journal title
Acta Neuropathologica CommunicationsVolume
2Issue
1AbstractIntraneuronal neurofibrillary tangles (NFTs) - a characteristic pathological feature of Alzheimer's and several other neurodegenerative diseases - are considered a major target for drug development. Tangle load correlates well with the severity of cognitive symptoms and mouse models of tauopathy are behaviorally impaired. However, there is little evidence that NFTs directly impact physiological properties of host neurons. Here we used a transgenic mouse model of tauopathy to study how advanced tau pathology in different brain regions affects activity-driven expression of immediate-early gene Arc required for experience-dependent consolidation of long-term memories. We demonstrate in vivo that visual cortex neurons with tangles are as likely to express comparable amounts of Arc in response to structured visual stimulation as their neighbors without tangles. Probability of experience-dependent Arc response was not affected by tau tangles in both visual cortex and hippocampal pyramidal neurons as determined postmortem. Moreover, whole brain analysis showed that network-wide activity-driven Arc expression was not affected by tau pathology in any of the brain regions, including brain areas with the highest tangle load. Our findings suggest that intraneuronal NFTs do not affect signaling cascades leading to experience-dependent gene expression required for long-term synaptic plasticity.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.Testing for dependence between failure time and visit compliance with interval-censored data
AbstractBetensky, R., Betensky, R. A., & Finkelstein, D. M. (n.d.).Publication year
2002Journal title
BiometricsVolume
58Issue
1Page(s)
58-63AbstractInterval-censored failure-time data arise when subjects miss prescheduled visits at which the failure is to be assessed. The resulting intervals in which the failure is known to have occurred are overlapping. Most approaches to the analysis of these data assume that the visit-compliance process is ignorable with respect to likelihood analysis of the failure-time distribution. While this assumption offers considerable simplification, it is not always plausible. Here we test for dependence between the failure- and visit-compliance processes, applicable to studies in which data collection continues after the occurrence of the failure. We do not make any of the assumptions made by previous authors about the joint distribution of the visit-compliance process, a covariate process, and the failure time. Instead, we consider conditional models of the true failure history given the current visit compliance at each visit time, allowing for correlation across visit times. Because failure status is not known at some visit times due to missed visits, only models of the observed failure history given current visit compliance are estimable. We describe how the parameters from these models can be used to test for a negative association and how bounds on unestimable parameters provided by the observed data are needed additionally to infer a positive association. We illustrate the method with data from an AIDS study and we investigate the power of the test through a simulation study.Testing goodness of fit of a uniform truncation model
AbstractMandel, M., & Betensky, R. (n.d.).Publication year
2007Journal title
BiometricsVolume
63Issue
2Page(s)
405-412AbstractSeveral goodness-of-fit tests of a lifetime distribution have been suggested in the literature; many take into account censoring and/or truncation of event times. In some contexts, a goodness-of-fit test for the truncation distribution is of interest. In particular, better estimates of the lifetime distribution can be obtained when knowledge of the truncation law is exploited. In cross-sectional sampling, for example, there are theoretical justifications for the assumption of a uniform truncation distribution, and several studies have used it to improve the efficiency of their survival estimates. The duality of lifetime and truncation in the absence of censoring enables methods for testing goodness of fit of the lifetime distribution to be used for testing goodness of fit of the truncation distribution. However, under random censoring, this duality does not hold and different tests are required. In this article, we introduce several goodness-of-fit tests for the truncation distribution and investigate their performance in the presence of censored event times using simulation. We demonstrate the use of our tests on two data sets.Testing quasi-independence of failure and truncation times via conditional kendall's tau
AbstractMartin, E. C., & Betensky, R. (n.d.).Publication year
2005Journal title
Journal of the American Statistical AssociationVolume
100Issue
470Page(s)
484-492AbstractTruncated survival data arise when the failure time is observed only if it falls within a subject-specific truncating set. Most analysis methods rely on the key assumption of quasi-independence, that is, factorization of the joint density of failure and truncation times into a product proportional to the individual densities in the observable region. Unlike independence of failure time and censoring time, quasi-independence can be tested. Tests of quasi-independence are available for one-sided truncation and for truncation that depends on a measured covariate, but not for more complex truncation schemes. Here tests of quasi-independenee based on a multivariate conditional Kendall's tau are proposed for doubly truncated data, bivariate left-truncated data, and other forms of truncated survival data that arise when initiating or terminating event times are interval-censored. Asymptotic properties under the null are derived. The tests are illustrated using several real datasets and evaluated via simulation.Tests for treatment group differences in the hazards for survival, before and after the occurrence of an intermediate event
AbstractBebchuk, J. D., & Betensky, R. (n.d.).Publication year
2005Journal title
Statistics in MedicineVolume
24Issue
3Page(s)
359-378AbstractIn many settings, one would expect that the hazard for a terminal event would change with the occurrence of an intermediate event. For example, in an AIDS clinical trial, it is of interest to assess whether there is a difference between treatments in the hazards for death prior to drop in Karnofsky performance score and in the hazards subsequent to the drop in Karnofsky score. Tests for the effect of treatment on these hazard functions, separately or jointly, are useful in conjunction with tests of overall survival. We consider four Cox regression models for the hazard function, constructed by allowing for various combinations of time-dependent stratification and time-dependent covariates, both of which are based on the occurrence of the intermediate event. Assuming a Markov transition model from the intermediate to the terminal event, partial likelihoods can be used for inference, enabling the use of standard statistical software for computation. We develop analytic approximations for the power of the derived score tests for treatment differences in the hazard functions and evaluate them through simulations. We apply our results to AIDS Clinical Trials Group (ACTG) protocol 021.Tests of association under misclassification : Application to histological sampling in oncology
AbstractBetensky, R., Louis, D. N., & Cairncross, J. G. (n.d.).Publication year
2007Journal title
Statistics in MedicineVolume
26Issue
26Page(s)
4808-4816AbstractSubjects in tumour studies are often misclassified with respect to histologic features that are not routinely recorded in diagnostic reports and that display heterogeneity within tumours. Pathologic analysis of the tumours may miss the feature of interest if the pathologist was not alerted to detail the microscopic feature of interest or if it is not present in the selected specimens. In this setting, only the subjects for whom the outcome is not found are potentially misclassified. Analyses of associations between the observed, potentially misclassified, outcome and a second outcome are invalid if the probability of misclassification depends on the second outcome. Three natural tests of association based on the observed data depend on different numbers of nuisance parameters. Most promising is a test based on the ratio of proportions of the observed feature. We illustrate this test using a study of the association of imaging parameters with genetic features in subjects with oligodendroglioma, a common brain tumour. In this study, calcification, a feature related to the imaging parameters, was potentially misclassified as not present.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.The association between measures of sleepiness and subjective cognitive decline symptoms in a diverse population of cognitively normal older adults
AbstractBriggs, A. Q., Boza-Calvo, C., Bernard, M. A., Rusinek, H., Betensky, R., & Masurkar, A. V. (n.d.).Publication year
2025Journal title
Journal of Alzheimer's DiseaseVolume
105Issue
3Page(s)
740-744AbstractSubjective cognitive decline (SCD) is associated with preclinical Alzheimer's disease (AD). Suboptimal sleep is also a risk factor for cognitive decline, but with unclear relationship to SCD. We conducted a retrospective cross-sectional study in a biracial research cohort of 148 cognitively normal older adults who underwent quantification of SCD (Cognitive Change Index; CCI), sleepiness (Epworth Sleepiness Scale; ESS), depression (Geriatric Depression Scale; GDS), and amyloid/tau PET. ESS score was associated with total, amnestic, and non-amnestic CCI scores, after adjustment for GDS, amyloid/tau burden, and race. This supports future longitudinal work on how sleepiness impacts SCD outcomes.The borderline or weakly positive Hybrid Capture II HPV test : A statistical and comparative (PCR) analysis
AbstractFederschneider, J. M., Yuan, L., Brodsky, J., Breslin, G., Betensky, R., & Crum, C. P. (n.d.).Publication year
2004Journal title
American Journal of Obstetrics and GynecologyVolume
191Issue
3Page(s)
757-761AbstractObjectives Recent studies have hypothesized that laboratory contamination may influence interpretation of Hybrid Capture II (HCII) human papillomavirus (HPV) detection assay values. Study design To test this hypothesis, 572 consecutive HCII samples were statistically evaluated to test the null hypothesis that cross-well contamination was not present. In addition, 874 consecutive paired samples from patients followed by both HCII and polymerase chain reaction (PCR) analysis were compared. Results A Kendall's tau measure of association among adjacent wells yielded a P value of .016, rejecting the null hypothesis of no contamination. Analysis of relative light unit values between 0.8 and 1.5 rejected the null hypothesis at P=.077. Moreover, PCR positivity was significantly higher for samples with HCII values above 1.5 vs 0.8 to 1.5 (P=.001). Conclusion Cross-well contamination of samples occurs during processing, and may influence interpretation of some borderline positives. The proportion of cases at risk is low (The distribution of survival times after injury
AbstractClark, D. E., Qian, J., Sihler, K. C., Hallagan, L. D., & Betensky, R. (n.d.).Publication year
2012Journal title
World Journal of SurgeryVolume
36Issue
7Page(s)
1562-1570AbstractIntroduction The distribution of survival times after injury has been described as "trimodal," but several studies have not confirmed this. The purpose of this study was to clarify the distribution of survival times after injury. Methods We defined survival time (t s) as the interval between injury time and declared death time. We constructed histograms for t s ≤ 150 min from the 2004-2007 Fatality Analysis Reporting System (FARS, for traffic crashes) and National Violent Death Reporting System (NVDRS, for homicides). We estimated statistical models in which death times known only within intervals were treated as interval-censored. For confirmation, we also obtained EMS response times (t r), prehospital times (t p), and hospital times (t h) for decedents in the 2008 National Trauma Data Bank (NTDB) with t s = t p + t h ≤ 150. We approximated times until circulatory arrest (t x) as t r for patients pulseless at the injury scene, t p for other patients pulseless at hospital admission, and t s for the rest; for any declared t s, we calculated mean t x/t s. We used this ratio to estimate t x for hospital deaths in FARS or NVDRS and provide independent support for using interval-censored methods. Results FARS andNVDRS deathsweremost frequent in the first few minutes. Both showed a second peak at 35-40 min after injury, corresponding to peaks in hospital deaths. Third peakswere not present. Estimated t x in FARS and NVDRS did not show second peaks and were similar to estimates treating some death times as interval-censored. Conclusions Increases in frequency of survival times at 35-40 min are primarily artifacts created because declaration of death in hospitals is delayed until completing resuscitative attempts. By avoiding these artifacts, interval censoring methods are useful for analysis of injury survival times.The effect of hospital care on early survival after penetrating trauma
AbstractClark, D. E., Doolittle, P. C., Winchell, R. J., & Betensky, R. (n.d.).Publication year
2014Journal title
Injury EpidemiologyVolume
1Issue
1Page(s)
1-9AbstractBackground: The effectiveness of emergency medical interventions can be best evaluated using time-to-event statistical methods with time-varying covariates (TVC), but this approach is complicated by uncertainty about the actual times of death. We therefore sought to evaluate the effect of hospital intervention on mortality after penetrating trauma using a method that allowed for interval censoring of the precise times of death. Methods: Data on persons with penetrating trauma due to interpersonal assault were combined from the 2008 to 2010 National Trauma Data Bank (NTDB) and the 2004 to 2010 National Violent Death Reporting System (NVDRS). Cox and Weibull proportional hazards models for survival time (tSURV) were estimated, with TVC assumed to have constant effects for specified time intervals following hospital arrival. The Weibull model was repeated with tSURV interval-censored to reflect uncertainty about the precise times of death, using an imputation method to accommodate interval censoring along with TVC. Results: All models showed that mortality was increased by older age, female sex, firearm mechanism, and injuries involving the head/neck or trunk. Uncensored models showed a paradoxical increase in mortality associated with the first hour in a hospital. The interval-censored model showed that mortality was markedly reduced after admission to a hospital, with a hazard ratio (HR) of 0.68 (95% CI 0.63, 0.73) during the first 30 min declining to a HR of 0.01 after 120 min. Admission to a verified level I trauma center (compared to other hospitals in the NTDB) was associated with a further reduction in mortality, with a HR of 0.93 (95% CI 0.82, 0.97). Conclusions: Time-to-event models with TVC and interval censoring can be used to estimate the effect of hospital care on early mortality after penetrating trauma or other acute medical conditions and could potentially be used for interhospital comparisons.The impact of amyloid-beta and tau on prospective cognitive decline in older individuals
AbstractSperling, R. A., Mormino, E. C., Schultz, A. P., Betensky, R., Papp, K. V., Amariglio, R. E., Hanseeuw, B. J., Buckley, R., Chhatwal, J., Hedden, T., Marshall, G. A., Quiroz, Y. T., Donovan, N. J., Jackson, J., Gatchel, J. R., Rabin, J. S., Jacobs, H., Yang, H. S., Properzi, M., … Johnson, K. A. (n.d.).Publication year
2019Journal title
Annals of NeurologyVolume
85Issue
2Page(s)
181-193AbstractObjectives: Amyloid-beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. Methods: One hundred thirty-seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. Results: Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. Interpretation: Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1–3 ANN NEUROL 2019;85:181–193.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; PThe Leapfrog Volume Criteria May Fall Short in Identifying High-Quality Surgical Centers
AbstractChristian, C. K., Gustafson, M. L., Betensky, R., Daley, J., Greenfield, L. J., Rhodes, R. S., & Zinner, M. J. (n.d.).Publication year
2003Journal title
Annals of SurgeryVolume
238Issue
4Page(s)
447-457AbstractObjective: The original Leapfrog Initiative recommends selective referral based on procedural volume thresholds (500 coronary artery bypass graft [CABG] surgeries, 30 abdominal aortic aneurysm [AAA] repairs, 100 carotid endarterectomies [CEA], and 7 esophagectomies annually). We tested the volume-mortality relationship for these procedures in the University HealthSystem Consortium (UHC) Clinical DatabaseSM, a database of all payor discharge abstracts from UHC academic medical center members and affiliates. We determined whether the Leapfrog thresholds represent the optimal cutoffs to discriminate between high- and low-mortality hospitals. Methods: Logistic regression was used to test whether volume was a significant predictor of mortality. Volume was analyzed in 3 different ways: as a continuous variable, a dichotomous variable (above and below the Leapfrog threshold), and a categorical variable. We examined all possible thresholds for volume and observed the optimal thresholds at which the odds ratio is the highest, representing the greatest difference in odds of death between the 2 groups of hospitals. Results: In multivariate analysis, a relationship between volume and mortality exists for AAA in all 3 models. For CABG, there is a strong relationship when volume is tested as a dichotomous or categorical variable. For CEA and esophagectomy, we were unable to identify a consistent relationship between volume and outcome. We identified empirical thresholds of 250 CABG, 15 AAA, and 22 esophagectomies, but were unable to find a meaningful threshold for CEA. Conclusions: In this group of academic medical centers and their affiliated hospitals, we demonstrated a significant relationship between volume and mortality for CABG and AAA but not for CEA and esophagectomy, based on the Leapfrog thresholds. We described a new methodology to identify optimal data-based volume thresholds that may serve as a more rational basis for selective referral.The missing indicator approach for censored covariates subject to limit of detection in logistic regression models
AbstractChiou, S. H., Betensky, R., & Balasubramanian, R. (n.d.).Publication year
2019Journal title
Annals of EpidemiologyVolume
38Page(s)
57-64AbstractPurpose: In several biomedical studies, one or more exposures of interest may be subject to nonrandom missingness because of the failure of the measurement assay at levels below its limit of detection. This issue is commonly encountered in studies of the metabolome using tandem mass spectrometry–based technologies. Owing to a large number of metabolites measured in these studies, preserving statistical power is of utmost interest. In this article, we evaluate the small sample properties of the missing indicator approach in logistic and conditional logistic regression models. Methods: For nested case-control or matched case control study designs, we evaluate the bias, power, and type I error associated with the missing indicator method using simulation. We compare the missing indicator approach to complete case analysis and several imputation approaches. Results: We show that under a variety of settings, the missing indicator approach outperforms complete case analysis and other imputation approaches with regard to bias, mean squared error, and power. Conclusions: For nested case-control and matched study designs of modest sample sizes, the missing indicator model minimizes loss of information and thus provides an attractive alternative to the oft-used complete case analysis and other imputation approaches.The neutrophil to lymphocyte ratio associates with markers of Alzheimer’s disease pathology in cognitively unimpaired elderly people
AbstractJacobs, T., Jacobson, S. R., Fortea, J., Berger, J. S., Vedvyas, A., Marsh, K., He, T., Gutierrez-Jimenez, E., Fillmore, N. R., Gonzalez, M., Figueredo, L., Gaggi, N. L., Plaska, C. R., Pomara, N., Blessing, E., Betensky, R., Rusinek, H., Zetterberg, H., Blennow, K., … Ramos-Cejudo, J. (n.d.).Publication year
2024Journal title
Immunity and AgeingVolume
21Issue
1AbstractBackground: An elevated neutrophil–lymphocyte ratio (NLR) in blood has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. Conclusions: We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart Study
AbstractRamos-Cejudo, J., Johnson, A. D., Beiser, A., Seshadri, S., Salinas, J., Berger, J. S., Fillmore, N. R., Do, N., Zheng, C., Kovbasyuk, Z., Ardekani, B. A., Bubu, O. M., Parekh, A., Convit, A., Betensky, R., Wisniewski, T. M., & Osorio, R. S. (n.d.).Publication year
2021Journal title
Frontiers in Aging NeuroscienceVolume
13AbstractObjective: Active neutrophils are important contributors to Alzheimer’s disease (AD) pathology through the formation of capillary stalls that compromise cerebral blood flow (CBF) and through aberrant neutrophil signaling that advances disease progression. The neutrophil to lymphocyte ratio (NLR) is a proxy of neutrophil-mediated inflammation, and higher NLR is found in persons diagnosed with clinical AD. The objective of this study was to investigate whether increased NLR in older adults is independently associated with the risk of subsequent dementia. Methods: We examined associations of baseline NLR with incident dementia risk in the community-based Framingham Heart Study (FHS) longitudinal cohorts. The association between NLR and risk of dementia was evaluated using the cumulative incidence function (CIF) and inverse probability-weighted Cox proportional cause-specific hazards regression models, with adjustment for age, sex, body mass index (BMI), systolic and diastolic blood pressure, diabetes, current smoking status, low-density lipoprotein (LDH), high-density lipoprotein (LDL), total cholesterol, triglycerides, and history of cardiovascular disease (CVD). Random forest survival models were used to evaluate the relative predictive value of the model covariates on dementia risk. Results: The final study sample included 1,648 participants with FHS (average age, 69 years; 56% women). During follow-up (median, 5.9 years), we observed 51 cases of incident dementia, of which 41 were AD cases. Results from weighted models suggested that the NLR was independently associated with incident dementia, and it was preceded in predictive value only by age, history of CVD, and blood pressure at baseline. Conclusion: Our study shows that individuals with higher NLR are at a greater risk of subsequent dementia during a 5.9-year follow-up period. Further evaluating the role of neutrophil-mediated inflammation in AD progression may be warranted.The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart Study
AbstractBetensky, R., Ramos-Cejudo, J., Johnson, A. D., Beiser, A., Seshadri, S., Salinas, J., Berger, J. S., Fillmore, N. R., Do, N., Zheng, C., Kovbasyuk, Z., Ardekani, B. A., Bubu, O. M., Parekh, A., Convit, A., Betensky, R. A., Wisniewski, T. M., & Osorio, R. S. (n.d.).Publication year
2021Journal title
Frontiers in aging neuroscienceVolume
13Page(s)
773984AbstractActive neutrophils are important contributors to Alzheimer's disease (AD) pathology through the formation of capillary stalls that compromise cerebral blood flow (CBF) and through aberrant neutrophil signaling that advances disease progression. The neutrophil to lymphocyte ratio (NLR) is a proxy of neutrophil-mediated inflammation, and higher NLR is found in persons diagnosed with clinical AD. The objective of this study was to investigate whether increased NLR in older adults is independently associated with the risk of subsequent dementia. We examined associations of baseline NLR with incident dementia risk in the community-based Framingham Heart Study (FHS) longitudinal cohorts. The association between NLR and risk of dementia was evaluated using the cumulative incidence function (CIF) and inverse probability-weighted Cox proportional cause-specific hazards regression models, with adjustment for age, sex, body mass index (BMI), systolic and diastolic blood pressure, diabetes, current smoking status, low-density lipoprotein (LDH), high-density lipoprotein (LDL), total cholesterol, triglycerides, and history of cardiovascular disease (CVD). Random forest survival models were used to evaluate the relative predictive value of the model covariates on dementia risk. The final study sample included 1,648 participants with FHS (average age, 69 years; 56% women). During follow-up (median, 5.9 years), we observed 51 cases of incident dementia, of which 41 were AD cases. Results from weighted models suggested that the NLR was independently associated with incident dementia, and it was preceded in predictive value only by age, history of CVD, and blood pressure at baseline. Our study shows that individuals with higher NLR are at a greater risk of subsequent dementia during a 5.9-year follow-up period. Further evaluating the role of neutrophil-mediated inflammation in AD progression may be warranted.The p-Value Requires Context, Not a Threshold
AbstractBetensky, R. (n.d.).Publication year
2019Journal title
American StatisticianVolume
73Issue
sup1Page(s)
115-117AbstractIt is widely recognized by statisticians, though not as widely by other researchers, that the p-value cannot be interpreted in isolation, but rather must be considered in the context of certain features of the design and substantive application, such as sample size and meaningful effect size. I consider the setting of the normal mean and highlight the information contained in the p-value in conjunction with the sample size and meaningful effect size. The p-value and sample size jointly yield 95% confidence bounds for the effect of interest, which can be compared to the predetermined meaningful effect size to make inferences about the true effect. I provide simple examples to demonstrate that although the p-value is calculated under the null hypothesis, and thus seemingly may be divorced from the features of the study from which it arises, its interpretation as a measure of evidence requires its contextualization within the study. This implies that any proposal for improved use of the p-value as a measure of the strength of evidence cannot simply be a change to the threshold for significance.The prognostic value of histopathologic lesions in native kidney biopsy specimens : Results from the Boston kidney biopsy cohort study
AbstractSrivastava, A., Palsson, R., Kaze, A. D., Chen, M. E., Palacios, P., Sabbisetti, V., Betensky, R., Steinman, T. I., Thadhani, R. I., McMahon, G. M., Stillman, I. E., Rennke, H. G., & Waikar, S. S. (n.d.).Publication year
2018Journal title
Journal of the American Society of NephrologyVolume
29Issue
8Page(s)
2213-2224AbstractBackground Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data. Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression ($40% eGFR decline or RRT). Results Mean baseline eGFR was 57.5636.0 ml/min per 1.73 m 2 . During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27). Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.The SIST-M : Predictive validity of a brief structured clinical dementia rating interview
AbstractOkereke, O. I., Pantoja-Galicia, N., Copeland, M., Hyman, B. T., Wanggaard, T., Albert, M. S., Betensky, R., & Blacker, D. (n.d.).Publication year
2012Journal title
Alzheimer disease and associated disordersVolume
26Issue
3Page(s)
225-231AbstractBackground: We have previously established the reliability and cross-sectional validity of the SIST-M (Structured Interview and Scoring Tool-Massachusetts Alzheimer's Disease Research Center), a shortened version of an instrument shown to predict progression to Alzheimer disease (AD), even among persons with very mild cognitive impairment (vMCI). Objective: To test the predictive validity of the SIST-M. Methods: Participants were 342 community-dwelling, nondemented older adults in a longitudinal study. Baseline Clinical Dementia Rating (CDR) ratings were determined by either (1) clinician interviews or (2) a previously developed computer algorithm based on 60 questions (of a possible 131) extracted from clinician interviews. We developed age+sex+education-adjusted Cox proportional hazards models using CDR-sum-of-boxes (CDR-SB) as the predictor, where CDR-SB was determined by either a clinician interview or an algorithm; models were run for the full sample (n=342) and among those jointly classified as vMCI using clinician-based and algorithm-based CDR ratings (n=156). We directly compared predictive accuracy using time-dependent receiver operating characteristic (ROC) curves. Results: AD hazard ratios (HRs) were similar for clinician-based and algorithm-based CDR-SB: for a 1-point increment in CDR-SB, the respective HRs [95% confidence interval (CI)] were 3.1 (2.5, 3.9) and 2.8 (2.2, 3.5); among those with vMCI, the respective HRs (95% CI) were 2.2 (1.6, 3.2) and 2.1 (1.5, 3.0). Similarly high predictive accuracy was achieved: the concordance probability (weighted average of the area-under-the-ROC curves) over follow-up was 0.78 versus 0.76 using clinician-based versus algorithm-based CDR-SB. Conclusion: CDR scores based on items from this shortened interview had high predictive ability for AD-comparable to that using a lengthy clinical interview.