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
Assumptions regarding right censoring in the presence of left truncation
AbstractQian, J., & Betensky, R. (n.d.).Publication year
2014Journal title
Statistics and Probability LettersVolume
87Issue
1Page(s)
12-17AbstractClinical studies using complex sampling often involve both truncation and censoring, where there are options for the assumptions of independence of censoring and event and for the relationship between censoring and truncation. In this paper, we clarify these choices, show certain equivalences, and provide examples.Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV
AbstractGrishchuk, Y., Sri, S., Rudinskiy, N., Ma, W., Stember, K. G., Cottle, M. W., Sapp, E., Difiglia, M., Muzikansky, A., Betensky, R., Wong, A. M., Bacskai, B. J., Hyman, B. T., Kelleher, R. J., Cooper, J. D., & Slaugenhaupt, S. A. (n.d.).Publication year
2014Journal title
Acta Neuropathologica CommunicationsVolume
2Issue
1AbstractMucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca2+]-imaging revealed no changes in resting [Ca2+] levels in Mcoln1 -/- cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition.Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes
AbstractSabbisetti, V. S., Waikar, S. S., Antoine, D. J., Smiles, A., Wang, C., Ravisankar, A., Ito, K., Sharma, S., Ramadesikan, S., Lee, M., De Jager, P. L., Ngo, T. T., Radlinski, M., Dear, J. W., Park, K. B., Betensky, R., Krolewski, A. S., & Bonventre, J. V. (n.d.).Publication year
2014Journal title
Journal of the American Society of NephrologyVolume
25Issue
10Page(s)
2177-2186AbstractCurrently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (PComputationally simple estimation and improved efficiency for special cases of double truncation
AbstractAustin, M. D., Simon, D. K., & Betensky, R. (n.d.).Publication year
2014Journal title
Lifetime Data AnalysisVolume
20Issue
3Page(s)
335-354AbstractDoubly truncated survival data arise when event times are observed only if they occur within subject specific intervals of times. Existing iterative estimation procedures for doubly truncated data are computationally intensive (Turnbull 38:290-295, 1976; Efron and Petrosian 94:824-825, 1999; Shen 62:835-853, 2010a). These procedures assume that the event time is independent of the truncation times, in the sample space that conforms to their requisite ordering. This type of independence is referred to as quasi-independence. In this paper we identify and consider two special cases of quasi-independence: complete quasi-independence and complete truncation dependence. For the case of complete quasi-independence, we derive the nonparametric maximum likelihood estimator in closed-form. For the case of complete truncation dependence, we derive a closed-form nonparametric estimator that requires some external information, and a semi-parametric maximum likelihood estimator that achieves improved efficiency relative to the standard nonparametric maximum likelihood estimator, in the absence of external information. We demonstrate the consistency and potentially improved efficiency of the estimators in simulation studies, and illustrate their use in application to studies of AIDS incubation and Parkinson's disease age of onset.Eliminating bias due to censoring in Kendall's tau estimators for quasi-independence of truncation and failure
AbstractAustin, M. D., & Betensky, R. (n.d.).Publication year
2014Journal title
Computational Statistics and Data AnalysisVolume
73Page(s)
16-26AbstractWhile the currently available estimators for the conditional Kendall's tau measure of association between truncation and failure are valid for testing the null hypothesis of quasi-independence, they are biased when the null does not hold. This is because they converge to quantities that depend on the censoring distribution. The magnitude of the bias relative to the theoretical Kendall's tau measure of association between truncation and failure due to censoring has not been studied, and so its importance in real problems is not known. We quantify this bias in order to assess the practical usefulness of the estimators. Furthermore, we propose inverse probability weighted versions of the conditional Kendall's tau estimators to remove the effects of censoring and provide asymptotic results for the estimators. In simulations, we demonstrate the decrease in bias achieved by these inverse probability weighted estimators. We apply the estimators to the Channing House data set and an AIDS incubation data set.Evidence-based decision support for neurological diagnosis reduces errors and unnecessary workup
AbstractSegal, M. M., Williams, M. S., Gropman, A. L., Torres, A. R., Forsyth, R., Connolly, A. M., El-Hattab, A. W., Perlman, S. J., Samanta, D., Parikh, S., Pavlakis, S. G., Feldman, L. K., Betensky, R., & Gospe, S. M. (n.d.).Publication year
2014Journal title
Journal of Child NeurologyVolume
29Issue
4Page(s)
487-492AbstractUsing vignettes of real cases and the SimulConsult diagnostic decision support software, neurologists listed a differential diagnosis and workup before and after using the decision support. Using the software, there was a significant reduction in error, up to 75% for diagnosis and 56% for workup. This error reduction occurred despite the baseline being one in which testers were allowed to use narrative resources and Web searching. A key factor that improved performance was taking enough time (>2 minutes) to enter clinical findings into the software accurately. Under these conditions and for instances in which the diagnoses changed based on using the software, diagnostic accuracy improved in 96% of instances. There was a 6% decrease in the number of workup items accompanied by a 34% increase in relevance. The authors conclude that decision support for a neurological diagnosis can reduce errors and save on unnecessary testing.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;75:597-601Synergistic 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 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.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.Variable importance in matched case-control studies in settings of high dimensional data
AbstractBalasubramanian, R., Andres Houseman, E., Coull, B. A., Lev, M. H., Schwamm, L. H., & Betensky, R. (n.d.).Publication year
2014Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
63Issue
4Page(s)
639-655AbstractSummary: We propose a method for assessing variable importance in matched case-control investigations and other highly stratified studies characterized by high dimensional data (p>>n). In simulated and real data sets, we show that the algorithm proposed performs better than a conventional univariate method (conditional logistic regression) and a popular multivariable algorithm (random forests) that does not take the matching into account. The methods are applicable to wide ranging, high impact clinical studies including metabolomic, proteomic studies and neuroimaging analyses, such as those assessing stroke and Alzheimer's disease. The methods proposed have been implemented in a freely available R library (http://cran.r-project.org/web/packages/RPCLR/index.html).Variable selection and prediction using a nested, matched case-control study : Application to hospital acquired pneumonia in stroke patients
AbstractQian, J., Payabvash, S., Kemmling, A., Lev, M. H., Schwamm, L. H., & Betensky, R. (n.d.).Publication year
2014Journal title
BiometricsVolume
70Issue
1Page(s)
153-163AbstractMatched case-control designs are commonly used in epidemiologic studies for increased efficiency. These designs have recently been introduced to the setting of modern imaging and genomic studies, which are characterized by high-dimensional covariates. However, appropriate statistical analyses that adjust for the matching have not been widely adopted. A matched case-control study of 430 acute ischemic stroke patients was conducted at Massachusetts General Hospital (MGH) in order to identify specific brain regions of acute infarction that are associated with hospital acquired pneumonia (HAP) in these patients. There are 138 brain regions in which infarction was measured, which introduce nearly 10,000 two-way interactions, and challenge the statistical analysis. We investigate penalized conditional and unconditional logistic regression approaches to this variable selection problem that properly differentiate between selection of main effects and of interactions, and that acknowledge the matching. This neuroimaging study was nested within a larger prospective study of HAP in 1915 stroke patients at MGH, which recorded clinical variables, but did not include neuroimaging. We demonstrate how the larger study, in conjunction with the nested, matched study, affords us the capability to derive a score for prediction of HAP in future stroke patients based on imaging and clinical features. We evaluate the proposed methods in simulation studies and we apply them to the MGH HAP study.An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials
AbstractMi, M. Y., & Betensky, R. (n.d.).Publication year
2013Journal title
Clinical TrialsVolume
10Issue
2Page(s)
207-215AbstractBackground Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample-size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Purpose Because the basic SPCD already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and whether we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Methods Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample-size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. Results From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample-size re-estimation, up to 25% power was recovered from underestimated sample-size scenarios. Limitations Given the numerous possible test parameters that could have been chosen for the simulations, the study's results are limited to situations described by the parameters that were used and may not generalize to all possible scenarios. Furthermore, dropout of patients is not considered in this study. Conclusions It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments.Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in alzheimer disease
AbstractSerrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R., Frosch, M. P., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Journal of Neuropathology and Experimental NeurologyVolume
72Issue
6Page(s)
462-471AbstractAlthough it is clear that astrocytes and microglia cluster around dense-core amyloid plaques in Alzheimer disease (AD), whether they are primarily attracted to amyloid deposits or are just reacting to plaque-associated neuritic damage remains elusive. We postulate that astrocytes and microglia may differentially respond to fibrillar amyloid β. Therefore, we quantified the size distribution of dense-core thioflavin-S (ThioS)-positive plaques in the temporal neocortex of 40 AD patients and the microglial and astrocyte responses in their vicinity (≤50 μm) and performed correlations between both measures. As expected, both astrocytes and microglia were clearly spatially associated with ThioS-positive plaques (p = 0.0001, ≤50 μm vs >50 μm from their edge), but their relationship to ThioS-positive plaque size differed: larger ThioS-positive plaques were associated with more surrounding activated microglia (p = 0.0026), but this effect was not observed with reactive astrocytes. Microglial response to dense-core plaques seems to be proportional to their size, which we postulate reflects a chemotactic effect of amyloid β. By contrast, plaque-associated astrocytic response does not correlate with plaque size and seems to parallel the behavior of plaque-associated neuritic damage.Estimating the effect of emergency care on early survival after traffic crashes
AbstractClark, D. E., Winchell, R. J., & Betensky, R. (n.d.).Publication year
2013Journal title
Accident Analysis and PreventionVolume
60Page(s)
141-147AbstractIntroduction Traffic crash mortality is higher in rural areas, but it is unclear whether this is due to greater injury severity, time delays, or Emergency Medical Services (EMS) deficiencies. Methods Data from 2002-2003 were combined from the Fatality Analysis Reporting System (FARS) and an "expanded version" of the National Automotive Sampling System (NASS) Crashworthiness Data System (CDS). Weighted Cox and Weibull models for survival time (tSURV) were estimated, with time-varying covariates (TVC) having constant effects for specified time intervals following EMS arrival time (tEMS) and hospital arrival time (tHOS). The Weibull model was repeated with tSURV interval-censored to reflect uncertainty about the exact time of death, using an imputation method to accommodate interval censoring along with TVC. Results FARS contained records for 92,718 persons with fatal or incapacitating injuries, and NASS/CDS contained 5517 (weighted population of 642,716) with incapacitating injuries. All models associated mortality with increasing age, male sex, belt nonuse, higher speeds, and vehicle rollover. The interval-censored model associated EMS intervention with a beneficial effect until tEMS + 30 min, but not thereafter; hospital intervention was associated with a strongly beneficial effect that increased with time. Rural location was associated with a higher baseline hazard; a 50% reduction in rural prehospital time would theoretically reduce 4-h mortality by about 7%. Conclusion Rural/urban disparity in crash mortality is mostly independent of time delays and EMS effects. However, survival models with TVC support clinical intuition of a "golden hour" in EMS care, and the importance of timely transport to a hospital.Estimating Time to Disease Progression Comparing Transition Models and Survival Methods-An Analysis of Multiple Sclerosis Data
AbstractMandel, M., Mercier, F., Eckert, B., Chin, P., & Betensky, R. (n.d.).Publication year
2013Journal title
BiometricsVolume
69Issue
1Page(s)
225-234AbstractThis article reports an analysis that aims to quantify the effect of fingolimod, an oral treatment for relapsing remitting multiple sclerosis (MS), on disability progression. The standard approach utilizes survival analysis methods, which may be problematic for MS studies that assess disability at only a few time points and include as a cardinal feature both relapses and remissions. Instead, a Markov transition model, originally developed in the framework of longitudinal data, is fit, and its special probabilistic properties are used to estimate survival curves for time to disability progression. The transition approach models the whole disability process and uses all available transition data for inference, while survival methods concentrate on a single event of interest and use only time to event data. This article compares the transition model approach to survival analysis methods, and discusses the differences in the interpretations of the estimated parameters. It applies both models to data obtained from two phase 3 clinical trials and finds that both yield positive effects for the new treatment compared to placebo, and provide similar estimates for the probability of disability progression over time. The transition model enables calculation of covariate-specific transition matrices that describe the short-term effect of treatment and other covariates on the disability process.Examination of the clinicopathologic continuum of Alzheimer disease in the autopsy cohort of the national alzheimer coordinating center
AbstractSerrano-Pozo, A., Qian, J., Monsell, S. E., Frosch, M. P., Betensky, R., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Journal of Neuropathology and Experimental NeurologyVolume
72Issue
12Page(s)
1182-1192AbstractTo test the hypothesis that Alzheimer disease (AD) is a clinical and pathologic continuum between normal aging and end-stage dementia, we selected a convenience sample of subjects from the National Alzheimer Coordinating Center 2005 to 2012 autopsy cohort (n = 2,083) with the last clinical evaluation within 2 years before autopsy and no other primary neuropathologic diagnosis. Demographic and neuropathologic characteristics were correlated with the Clinical Dementia Rating-Sum of Boxes in the 835 subjects meeting these criteria. Both neuritic plaques and neurofibrillary tangles independently predicted Clinical Dementia Rating-Sum of Boxes. Severe small-vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also independently associated with the degree of cognitive impairment. By contrast, education was a strong independent protective factor against cognitive deficits. The cause of mild to moderate dementia remained uncertain in 14% of the patients. Inverse probability weighting suggests the generalizability of these results to nonautopsied cohorts. These data indicate that plaques and tangles independently contribute to cognitive impairment, that concurrent vascular disease strongly correlates with cognitive dysfunction even in a sample selected to represent the AD pathologic continuum, and that education further modifies clinical expression. Thus, multiple concomitant etiologies of brain damage and premorbid characteristics contribute to the uncertainty of AD clinicopathologic correlations based only on tangles and plaques.Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain
AbstractHudry, E., Dashkoff, J., Roe, A. D., Takeda, S., Koffie, R. M., Hashimoto, T., Scheel, M., Spires-Jones, T., Arbel-Ornath, M., Betensky, R., Davidson, B. L., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Science Translational MedicineVolume
5Issue
212AbstractInheritance of the ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor associated with the sporadic form of Alzheimer's disease (AD), whereas the rare APOE ε2 allele has the opposite effect. However, the mechanisms whereby APOE confers risk and protection remain uncertain. We used a gene transfer approach to bathe the cortex of amyloid plaque-bearing transgenic mice with virally expressed human APOE. We monitored amyloid-β (Aβ) with multiphoton imaging, in vivo microdialysis, and postmortem array tomography to study the kinetics of human APOE mediated changes in Aβ-related neurotoxicity in a mouse model of AD. We observed that human APOE4 increased the concentrations of oligomeric Aβ within the interstitial fluid and exacerbated plaque deposition; the converse occurred after exposure to human APOE2. Peri-plaque synapse loss and dystrophic neurites were also worsened by APOE4 or attenuated by APOE2. Egress of Aβ from the central nervous system (CNS) into the plasma was diminished by APOE3 and APOE4 compared to APOE2, in accord with isoform-specific retention of Aβ in the CNS. Overall, our data show a differential effect of human APOE isoforms on amyloid deposition and clearance in transgenic mice and, more importantly, on Aβ-mediated synaptotoxicity. These results suggest that the APOE genetic risk is mediated by Aβ, and that therapeutic approaches aimed at decreasing APOE4, or increasing APOE2, may be beneficial in AD.Hospital Acquired Pneumonia Is Linked to Right Hemispheric Peri-Insular Stroke
AbstractKemmling, A., Lev, M. H., Payabvash, S., Betensky, R., Qian, J., Masrur, S., & Schwamm, L. H. (n.d.).Publication year
2013Journal title
PloS oneVolume
8Issue
8AbstractPurpose:Hospital acquired pneumonia (HAP) is a major complication of stroke. We sought to determine associations between infarction of specific brain regions and HAP.Methods:215 consecutive acute stroke patients with HAP (2003-2009) were carefully matched with 215 non-pneumonia controls by gender, then NIHSS, then age. Admission imaging and binary masks of infarction were registered to MNI-152 space. Regional atlas and voxel-based log-odds were calculated to assess the relationship between infarct location and the likelihood of HAP. An independently validated penalized conditional logistic regression model was used to identify HAP associated imaging regions.Results:The HAP and control patients were well matched by gender (100%), age (95% within 5-years), NIHSS (98% within 1-point), infarct size, dysphagia, and six other clinical variables. Right hemispheric infarcts were more frequent in patients with HAP versus controls (43.3% vs. 34.0%, p = 0.054), whereas left hemispheric infarcts were more frequent in controls (56.7% vs. 44.7%, p = 0.012); there was no significant difference between groups in the rate of brainstem strokes (p = 1.0). Of the 10 most infarcted regions, only right insular cortex volume was different in HAP versus controls (20 vs. 12 ml, p = 0.02). In univariate analyses, the highest log-odds regions for pneumonia were right hemisphere, cerebellum, and brainstem. The best performing multivariate model selected 7 brain regions of infarction and 2 infarct volume-based variables independently associated with HAP.Conclusions:HAP is associated with right hemispheric peri-insular stroke. These associations may be related to autonomic modulation of immune mechanisms, supporting recent hypotheses of stroke mediated immune suppression.Human miRNome profiling identifies microRNAs differentially present in the urine after kidney injury
AbstractRamachandran, K., Saikumar, J., Bijol, V., Koyner, J. L., Qian, J., Betensky, R., Waikar, S. S., & Vaidya, V. S. (n.d.).Publication year
2013Journal title
Clinical ChemistryVolume
59Issue
12Page(s)
1742-1752AbstractBACKGROUND: Extracellular microRNAs (miRNAs) have been proposed as potentially robust and stable biomarkers of various disease conditions. The primary objective of this study was to identify miRNAs differentially occurring in the urine that could serve as potential biomarkers of acute kidney injury (AKI), because traditional AKI markers have limitations with respect to sensitivity, specificity, and timeliness of diagnosis. METHODS: We profiled 1809 miRNAs in pooled urine samples from 6 patients with AKI and from 6 healthy controls. We measured the 378 stably detectable miRNAs in the 12 samples individually and selected the top 7 miRNAs that were most different in the urine of patients with AKI compared with the non-AKI control individuals. These miRNAs were assessed in a larger cohort of patients with AKI (n = 98: 71 AKI patients in the intensive care unit (ICU) and 27 kidney transplantation patients with biopsy-proven tubular injury) and patients without AKI (n = 97: 74 healthy volunteers and 23 ICU patients without AKI). RESULTS: We identified 4 miRNAs capable of significantly differentiating patients with AKI from individuals without AKI: miR-21 (P = 0.0005), miR-200c (P < 0.0001), miR-423 (P = 0.001), and miR-4640 (P = 0.0355). The combined cross-validated area under the ROC curve for these 4 miRNAs was 0.91. The imprecision with respect to miRNA isolation and reverse transcription efficiency wasImperfect gold standards for biomarker evaluation
AbstractWaikar, S. S., Betensky, R., Emerson, S. C., & Bonventre, J. V. (n.d.).Publication year
2013Journal title
Clinical TrialsVolume
10Issue
5Page(s)
696-700AbstractBackground Serum creatinine has been used as the diagnostic test for acute kidney injury (AKI) for decades despite having imperfect sensitivity and specificity. Novel tubular injury biomarkers may revolutionize the diagnosis of KI; however, even if a novel tubular injury biomarker is 100% sensitive and 100% specific, it may appear inaccurate when using serum creatinine as the gold standard. Conclusions In general, the apparent diagnostic performance of a biomarker depends not only on its ability to detect injury but also on disease prevalence and the sensitivity and specificity of the imperfect gold standard. Apparent errors in diagnosis using a new biomarker may be a reflection of errors in the imperfect gold standard itself rather than poor performance of the biomarker. Clinical Trials 2013; 10: 696700. http://ctj.sagepub.com.Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints
AbstractMacklin, E. A., Blacker, D., Hyman, B. T., & Betensky, R. (n.d.).Publication year
2013Journal title
Journal of Alzheimer's DiseaseVolume
36Issue
3Page(s)
475-486AbstractAlzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n = 6,243). To identify a 'mid-risk' subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases.Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models
AbstractArbel-Ornath, M., Hudry, E., Eikermann-Haerter, K., Hou, S., Gregory, J. L., Zhao, L., Betensky, R., Frosch, M. P., Greenberg, S. M., & Bacskai, B. J. (n.d.).Publication year
2013Journal title
Acta NeuropathologicaVolume
126Issue
3Page(s)
353-364AbstractThe interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance; however, it has never been demonstrated directly. The accumulation of amyloid β (Aβ) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Aβ drainage along perivascular spaces has been postulated to be one of the mechanisms that mediate the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Aβ clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to Alzheimer disease and cerebral amyloid angiopathy.Molecular 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.Patients with celiac disease have a lower prevalence of non-insulin-dependent diabetes mellitus and metabolic syndrome
AbstractKabbani, T. A., Kelly, C. P., Betensky, R., Hansen, J., Pallav, K., Villafuerte-Gálvez, J. A., Vanga, R., Mukherjee, R., Novero, A., Dennis, M., & Leffler, D. A. (n.d.).Publication year
2013Journal title
GastroenterologyVolume
144Issue
5Page(s)
912-917.e1AbstractBackground & Aims: We investigated whether risk for non-insulin-dependent diabetes mellitus (NIDDM) and metabolic syndrome are affected by celiac disease. We examined the prevalence of NIDDM and metabolic syndrome among adults with celiac disease, compared with matched controls. Methods: We assessed medical records of 840 patients with biopsy-proven celiac disease for diagnoses of NIDDM, hypertension, or hyperlipidemia; body mass index (BMI); lipid profile; and levels of glucose or glycosylated hemoglobin, to identify those with metabolic syndrome. Patients without celiac disease were matched for age, sex, and ethnicity (n = 840 controls). The prevalence of NIDDM and metabolic syndrome in the celiac disease cohort was compared with that of the controls and subjects included in the National Health and Nutrition Examination Survey. Results: Twenty-six patients with celiac disease (3.1%) had NIDDM compared with 81 controls (9.6%) (P