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
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. A., 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.Threshold regression to accommodate a censored covariate
AbstractQian, J., Chiou, S. H., Maye, J. E., Atem, F., Johnson, K. A., & Betensky, R. A. (n.d.).Publication year
2018Journal title
BiometricsVolume
74Issue
4Page(s)
1261-1270AbstractIn several common study designs, regression modeling is complicated by the presence of censored covariates. Examples of such covariates include maternal age of onset of dementia that may be right censored in an Alzheimer's amyloid imaging study of healthy subjects, metabolite measurements that are subject to limit of detection censoring in a case-control study of cardiovascular disease, and progressive biomarkers whose baseline values are of interest, but are measured post-baseline in longitudinal neuropsychological studies of Alzheimer's disease. We propose threshold regression approaches for linear regression models with a covariate that is subject to random censoring. Threshold regression methods allow for immediate testing of the significance of the effect of a censored covariate. In addition, they provide for unbiased estimation of the regression coefficient of the censored covariate. We derive the asymptotic properties of the resulting estimators under mild regularity conditions. Simulations demonstrate that the proposed estimators have good finite-sample performance, and often offer improved efficiency over existing methods. We also derive a principled method for selection of the threshold. We illustrate the approach in application to an Alzheimer's disease study that investigated brain amyloid levels in older individuals, as measured through positron emission tomography scans, as a function of maternal age of dementia onset, with adjustment for other covariates. We have developed an R package, censCov, for implementation of our method, available at CRAN.Time-to-event data with time-varying biomarkers measured only at study entry, with applications to Alzheimer's disease
Failed generating bibliography.AbstractPublication year
2018Journal title
Statistics in MedicineVolume
37Issue
6Page(s)
914-932AbstractRelating time-varying biomarkers of Alzheimer's disease to time-to-event using a Cox model is complicated by the fact that Alzheimer's disease biomarkers are sparsely collected, typically only at study entry; this is problematic since Cox regression with time-varying covariates requires observation of the covariate process at all failure times. The analysis might be simplified by using study entry as the time origin and treating the time-varying covariate measured at study entry as a fixed baseline covariate. In this paper, we first derive conditions under which using an incorrect time origin of study entry results in consistent estimation of regression parameters when the time-varying covariate is continuous and fully observed. We then derive conditions under which treating the time-varying covariate as fixed at study entry results in consistent estimation. We provide methods for estimating the regression parameter when a functional form can be assumed for the time-varying biomarker, which is measured only at study entry. We demonstrate our analytical results in a simulation study and apply our methods to data from the Rush Religious Orders Study and Memory and Aging Project and data from the Alzheimer's Disease Neuroimaging Initiative.APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts
AbstractQian, J., Wolters, F. J., Beiser, A., Haan, M., Ikram, M. A., Karlawish, J., Langbaum, J. B., Neuhaus, J. M., Reiman, E. M., Roberts, J. S., Seshadri, S., Tariot, P. N., Woods, B. M. C., Betensky, R. A., & Blacker, D. (n.d.).Publication year
2017Journal title
PLoS MedicineVolume
14Issue
3AbstractBackground: With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer’s Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals. Methods and findings: We included cognitively unimpaired individuals aged 60–75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer’s Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60–64, 65–69, 70–75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60–64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65–69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70–75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80–85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%–38.45% at age 60–64 y, 30.76%–40.26% at 65–69 y, and 33.3%–35.17% at 70–75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables. Conclusions: Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies—with implications for informed consent and design for clinical trials targeting high-risk individuals.Association of cancer and Alzheimer's disease risk in a national cohort of veterans
AbstractFrain, L., Swanson, D., Cho, K., Gagnon, D., Lu, K. P., Betensky, R. A., & Driver, J. (n.d.).Publication year
2017Journal title
Alzheimer's and DementiaVolume
13Issue
12Page(s)
1364-1370AbstractIntroduction: To examine the risk of Alzheimer's disease (AD) among cancer survivors in a national database. Methods: Retrospective cohort of 3,499,378 mostly male US veterans aged ≥65 years were followed between 1996 and 2011. We used Cox models to estimate risk of AD and alternative outcomes (non-AD dementia, osteoarthritis, stroke, and macular degeneration) in veterans with and without a history of cancer. Results: Survivors of a wide variety of cancers had modestly lower AD risk, but increased risk of the alternative outcomes. Survivors of screened cancers, including prostate cancer, had a slightly increased AD risk. Cancer treatment was independently associated with decreased AD risk; those who received chemotherapy had a lower risk than those who did not. Discussion: Survivors of some cancers have a lower risk of AD but not other age-related conditions, arguing that lower AD diagnosis is not simply due to bias. Cancer treatment may be associated with decreased risk of AD.Bayesian Variable Selection Methods for Matched Case-Control Studies
AbstractAsafu-Adjei, J., Mahlet, G. T., Coull, B., Balasubramanian, R., Lev, M., Schwamm, L., & Betensky, R. (n.d.).Publication year
2017Journal title
International Journal of BiostatisticsVolume
13Issue
1AbstractMatched case-control designs are currently used in many biomedical applications. To ensure high efficiency and statistical power in identifying features that best discriminate cases from controls, it is important to account for the use of matched designs. However, in the setting of high dimensional data, few variable selection methods account for matching. Bayesian approaches to variable selection have several advantages, including the fact that such approaches visit a wider range of model subsets. In this paper, we propose a variable selection method to account for case-control matching in a Bayesian context and apply it using simulation studies, a matched brain imaging study conducted at Massachusetts General Hospital, and a matched cardiovascular biomarker study conducted by the High Risk Plaque Initiative.Cognitive resilience in clinical and preclinical Alzheimer’s disease: the Association of Amyloid and Tau Burden on cognitive performance
AbstractRentz, D. M., Mormino, E. C., Papp, K. V., Betensky, R. A., Sperling, R. A., & Johnson, K. A. (n.d.).Publication year
2017Journal title
Brain Imaging and BehaviorVolume
11Issue
2Page(s)
383-390AbstractWe explored the cross-sectional relationships between β-amyloid (Aβ) and inferior temporal tau deposition (IFT Tau) on cognitive performance and whether cognitive reserve (CR) modifies these associations. We studied 156 participants classified into groups of clinically normal (CN = 133), mild cognitive impairment (MCI = 17) and Alzheimer disease (AD = 6) dementia. AMNART IQ served as a proxy of CR and cognitive performance was assessed using the MMSE. In separate linear regression models predicting MMSE, we examined the interactions of CR x global Aβ and CR x IFT tau across all participants and within the CN group alone. In the whole sample, the interaction between CR and IFT tau was significant (p < 0.003), such that higher CR participants with elevated IFT tau had better MMSE scores compared with low CR participants with similar levels of IFT tau. The interaction between CR and Aβ status did not reach significance (p = 0.093). In CN only, no cross-sectional interactions among CR, Aβ, and IFT tau were observed on MMSE. These findings imply that CR may be protective against early AD processes and enable some individuals to remain cognitively stable despite elevated tau and Aβ burden.Correlation among baseline variables yields non-uniformity of p-values
AbstractBetensky, R. A., & Chiou, S. H. (n.d.).Publication year
2017Journal title
PloS oneVolume
12Issue
9AbstractA recent paper in Neurology used statistical techniques to investigate the integrity of the randomization in 33 clinical trials conducted by a group of investigators. Without justification, the approach assumed that there would be no impact of correlation among baseline variables. We investigated the impact of correlation on the conclusions of the approach in several large-scale simulation studies that replicated the sample sizes and baseline variables of the clinical trials in question and utilized proper randomization. Additionally, we considered scenarios with larger numbers of baseline variables. We found that, with even moderate correlation, there can be substantial inflation of the type I error of statistical tests of randomization integrity. This is also the case under no correlation, in the presence of some discrete baseline variables, with a large number of variables. Thus, statistical techniques for assessing randomization integrity should be applied with extreme caution given that very low p-values, which are taken as evidence against valid randomization, can arise even in the case of valid randomization, in the presence of correlation. More generally, the use of tests of goodness of fit to uniformity for the purpose of testing a global null hypothesis is not advisable in the presence of correlation.Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline
AbstractHanseeuw, B. J., Betensky, R. A., Schultz, A. P., Papp, K. V., Mormino, E. C., Sepulcre, J., Bark, J. S., Cosio, D. M., LaPoint, M., Chhatwal, J. P., Rentz, D. M., Sperling, R. A., & Johnson, K. A. (n.d.).Publication year
2017Journal title
Annals of NeurologyVolume
81Issue
4Page(s)
583-596AbstractObjective: The aim of this article was to evaluate in normal older adults and preclinical Alzheimer's disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline. Methods: We acquired positron emission tomography using F18 flortaucipir (tau), C11 Pittsburgh compound B (amyloid), and F18 fluorodeoxyglucose (FDG) in 90 clinically normal elderly of the Harvard Aging Brain Study. Results: Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly. In contrast, frontal hypometabolism related to the common age-related entorhinal tauopathy, but this dysfunction was independent of amyloid, and did not predict significant memory decline. Neocortical tauopathy was positively associated with metabolism in individuals with subthreshold amyloid, suggesting that glucose metabolism increases before decreasing in the course of preclinical AD. Interpretation: Our study identified a synergistic effect of amyloid and tau deposits and demonstrated, for the first time, in normal elderly its link to AD-like hypometabolism and to AD-like memory decline. The amyloid effect was observed with tau in neocortex, but not with tau in entorhinal cortex, which is the common site of age-related tauopathy. Entorhinal tau was associated with frontal hypometabolism, but this dysfunction was not associated with memory loss. Ann Neurol 2017;81:583–596.Is this significant?
Betensky, R. A. (n.d.).Publication year
2017Journal title
Annals of NeurologyVolume
81Issue
3Page(s)
344-347Linear regression with a randomly censored covariate: application to an Alzheimer's study
AbstractAtem, F. D., Qian, J., Maye, J. E., Johnson, K. A., & Betensky, R. A. (n.d.).Publication year
2017Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
66Issue
2Page(s)
313-328AbstractThe association between maternal age of onset of dementia and amyloid deposition (measured by in vivo positron emission tomography imaging) in cognitively normal older offspring is of interest. In a regression model for amyloid, special methods are required because of the random right censoring of the covariate of maternal age of onset of dementia. Prior literature has proposed methods to address the problem of censoring due to assay limit of detection, but not random censoring. We propose imputation methods and a survival regression method that do not require parametric assumptions about the distribution of the censored covariate. Existing imputation methods address missing covariates, but not right-censored covariates. In simulation studies, we compare these methods with the simple, but inefficient, complete-case analysis, and with thresholding approaches. We apply the methods to the Alzheimer's study.Neurofibrillary tangle stage and the rate of progression of Alzheimer symptoms: Modeling using an autopsy cohort and application to clinical trial design
AbstractQian, J., Hyman, B. T., & Betensky, R. A. (n.d.).Publication year
2017Journal title
JAMA NeurologyVolume
74Issue
5Page(s)
540-548AbstractIMPORTANCE The heterogeneity of rate of clinical progression among patients with Alzheimer disease leads to difficulty in providing clinical counseling and diminishes the power of clinical trials using disease-modifying agents. OBJECTIVE To gain a better understanding of the factors that affect the natural history of progression in Alzheimer disease for the purpose of improving both clinical care and clinical trial design. DESIGN, SETTING, AND PARTICIPANTS A longitudinal cohort study of aging from 2005 to 2014 in the National Alzheimer Coordinating Center. Clinical evaluation of the participants was conducted in 31 National Institute on Aging's Alzheimer Disease Centers. Nine hundred eighty-four participants in the National Alzheimer Coordinating Center cohort study who died and underwent autopsy and met inclusion and exclusion criteria. MAIN OUTCOMES AND MEASURES We sought to model the possibility that knowledge of neurofibrillary tangle burden in the presence of moderate or frequent plaques would add to the ability to predict clinical rate of progression during the ensuing 2 to 3 years.We examined the National Alzheimer Coordinating Center autopsy data to evaluate the effect of different neurofibrillary tangle stages on the rates of progression on several standard clinical instruments: the Clinical Dementia Rating Scale sum of boxes, a verbal memory test (logical memory), and a controlled oral word association task (vegetable naming), implementing a reverse-time longitudinal modeling approach in conjunction with latent class estimation to adjust for unmeasured sources of heterogeneity. RESULTS Several correlations between clinical variables and neurocognitive performance suggest a basis for heterogeneity: Higher education level was associated with lower Clinical Dementia Rating Scale sum of boxes (β = -0.19; P < .001), and frequent vs moderate neuritic plaques were associated with higher Clinical Dementia Rating Scale sum of boxes (β = 1.64; P < .001) and lower logical memory score (β = -1.07; P = .005). The rate of change of the clinical and cognitive scores varied depending on Braak stage, when adjusting for plaques, age of death, sex, education, and APOE genotype. For example, comparing high vs low Braak stage with other variables fixed, the logical memory score decreased a substantial 0.38 additional units per year (95%CI, -0.70 to -0.06; P = .02). Using these data, we estimate that a 300-participant clinical trial with end point of a 20% improvement in slope in rate of change of Clinical Dementia Rating Scale sum of boxes has 89%power when all participants in the trial are from the high Braak stage, compared with 29% power if Braak stage had not used for eligibility. CONCLUSIONS AND RELEVANCE We found that knowledge of neurofibrillary tangle stage, modeled as the sort of information that could be available from tau positron-emission tomography scans and its use to determine eligibility to a trial, could dramatically improve the power of clinical trials and equivalently reduce the required sample sizes of clinical trials.Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain
AbstractArbel-Ornath, M., Hudry, E., Boivin, J. R., Hashimoto, T., Takeda, S., Kuchibhotla, K. V., Hou, S., Lattarulo, C. R., Belcher, A. M., Shakerdge, N., Trujillo, P. B., Muzikansky, A., Betensky, R. A., Hyman, B. T., & Bacskai, B. J. (n.d.).Publication year
2017Journal title
Molecular NeurodegenerationVolume
12Issue
1AbstractBackground: Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer’s disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes. Method: To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging. Results: We observed a dramatic increase in the levels of neuronal resting calcium, which was dependent upon extracellular calcium influx and activation of NMDA receptors. Ryanodine receptors, previously implicated in AD models, did not appear to be primarily involved using this experimental setting. We used the high resolution cortical volumes acquired in-vivo to measure the effect on synaptic densities and observed that, while spine density remained stable within the first hour of oAβ exposure, a significant decrease in the number of dendritic spines was observed 24 h post treatment, despite restoration of intraneuronal calcium levels at this time point. Conclusions: These observations demonstrate a specific effect of oAβ on NMDA-mediated calcium influx, which triggers synaptic collapse in vivo. Moreover, this work leverages a method to quantitatively measure calcium concentration at the level of neuronal processes, cell bodies and single synaptic elements repeatedly and thus can be applicable to testing putative drugs and/or other intervention methodologies.A concept-wide association study of clinical notes to discover new predictors of kidney failure
AbstractSingh, K., Betensky, R. A., Wright, A., Curhan, G. C., Bates, D. W., & Waikar, S. S. (n.d.).Publication year
2016Journal title
Clinical Journal of the American Society of NephrologyVolume
11Issue
12Page(s)
2150-2158AbstractBackground and objectives Identifying predictors of kidney disease progression is critical toward the development of strategies to prevent kidney failure. Clinical notes provide a unique opportunity for big data approaches to identify novel risk factors for disease. Design, setting, participants, &measurements Weusednatural language processing tools to extract concepts from the preceding year’s clinical notes among patients newly referred to a tertiary care center’s outpatient nephrology clinics and retrospectively evaluated these concepts as predictors for the subsequent development of ESRD using proportional subdistribution hazards (competing risk) regression. The primary outcome was time to ESRD, accounting for a competing risk of death. We identified predictors from univariate and multivariate (adjusting for Tangri linear predictor) models using a5%threshold for falsediscovery rate (q value, 0.05).Weincluded allpatients seen by an adult outpatient nephrologist between January 1, 2004 and June 18, 2014 and excluded patients seen only by transplant nephrology, with preexisting ESRD, with fewer than five clinical notes, with no follow-up, or with no baseline creatinine values. Results Among the 4013 patients selected in the final study cohort, we identified 960 concepts in the unadjusted analysis and 885 concepts in the adjusted analysis. Novel predictors identified included high-dose ascorbic acid (adjusted hazard ratio, 5.48; 95%confidence interval, 2.80 to 10.70; q, 0.001) and fast food (adjusted hazard ratio, 4.34; 95% confidence interval, 2.55 to 7.40; q, 0.001). Conclusions Novel predictors of human disease may be identified using an unbiased approach to analyze text from the electronic health record.Comparison of urine output among patients treated with more intensive versus less intensive RRT: Results from the acute renal failure trial network study
AbstractMcCausland, F. R., Asafu-Adjei, J., Betensky, R. A., Palevsky, P. M., & Waikar, S. S. (n.d.).Publication year
2016Journal title
Clinical Journal of the American Society of NephrologyVolume
11Issue
8Page(s)
1335-1342AbstractBackground and objectives Intensive RRT may have adverse effects that account for the absence of benefit observed in randomized trials of more intensive versus less intensive RRT. We wished to determine the association of more intensive RRT with changes in urine output as a marker of worsening residual renal function in critically ill patients with severe AKI. Design, setting, participants, & measurements The Acute Renal Failure Trial Network Study (n=1124) was a multicenter trial that randomized critically ill patients requiring initiation of RRT tomore intensive (hemodialysis or sustained low-efficiency dialysis six times per week or continuous venovenous hemodiafiltration at 35 ml/kg per hour) versus less intensive (hemodialysis or sustained low-efficiency dialysis three times per week or continuous venovenous hemodiafiltration at 20 ml/kg per hour) RRT. Mixed linear regression models were fit to estimate the association of RRT intensity with change in daily urine output in survivors through day 7 (n=871); Cox regression models were fit to determine the association of RRT intensity with time to ≥50% decline in urine output in all patients through day 28. Results Mean age of participants was 60615 years old, 72% were men, and 30% were diabetic. In unadjusted models, among patients who survived ≥7 days, mean urine output was, on average, 31.7 ml/d higher (95% confidence interval, 8.2 to 55.2 ml/d) for the less intensive group compared with the more intensive group (P=0.01). More intensive RRT was associated with 29% greater unadjusted risk of decline in urine output of ≥50% (hazard ratio, 1.29; 95% confidence interval, 1.10 to 1.51). Conclusions More intensive versus less intensive RRT is associated with a greater reduction in urine output during the first 7 days of therapy and a greater risk of developing a decline in urine output of ≥50%in critically ill patients with severe AKI.Decreased hippocampal metabolism in high-amyloid mild cognitive impairment
AbstractHanseeuw, B. J., Schultz, A. P., Betensky, R. A., Sperling, R. A., & Johnson, K. A. (n.d.).Publication year
2016Journal title
Alzheimer's and DementiaVolume
12Issue
12Page(s)
1288-1296AbstractIntroduction Hippocampal volume (HV), cortical metabolism, and thickness are decreased in mild cognitive impairment (MCI). Hippocampal metabolism (HM) studies comparing MCI and clinically normal (CN) elderly gave inconsistent results. As hippocampus is a key region in Alzheimer's disease, we hypothesized that HM is specifically decreased in high-amyloid MCI. Methods Overall, 250 CN and 45 MCI underwent three-dimensional magnetic resonance imaging, fludeoxyglucose-positron emission tomography, and fluorodeoxyglucose-positron emission tomography (PET), and Pittsburgh Compound B (PiB) PET. We investigated the interaction between clinical and amyloid status on HM, HV, cortical metabolism, and thickness using linear models, covarying age, gender, and education. Analyses were conducted with and without correction for multiple comparisons and for partial volume effects. Results Volume-adjusted HM was decreased in high-amyloid MCI but close to normal in low-amyloid MCI and in high-amyloid CN. Both MCI groups had hippocampal atrophy, although less severe in low-amyloid MCI. High-amyloid CN and high-amyloid MCI had cortical hypometabolism. Discussion HM is decreased when both cognitive impairment and amyloid are present.Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly
AbstractDhilla Albers, A., Asafu-Adjei, J., Delaney, M. K., Kelly, K. E., Gomez-Isla, T., Blacker, D., Johnson, K. A., Sperling, R. A., Hyman, B. T., Betensky, R. A., Hastings, L., & Albers, M. W. (n.d.).Publication year
2016Journal title
Annals of NeurologyVolume
80Issue
6Page(s)
846-857AbstractObjective: The objective of this study was to relate a novel test of identifying and recalling odor percepts to biomarkers of Alzheimer's disease (AD) in well-characterized elderly individuals, ranging from cognitively normal to demented. Methods: One hundred eighty-three participants (cognitively normal: n = 70; subjective cognitive concerns: n = 74; mild cognitive impairment [MCI]: n = 29, AD dementia: n = 10) were administered novel olfactory tests: the Odor Percept IDentification (OPID) and the Percepts of Odor Episodic Memory (POEM) tests. Univariate cross-sectional analyses of performance across diagnoses; logistic regression modeling, including covariates of age, sex, education, APOE genotype, and neuropsychological test scores; and linear mixed modeling of longitudinal cognitive scores were performed. Amyloid deposition and MRI volumetrics were analyzed in a subset of participants. Results: Accuracy of identification and episodic memory of odor percepts differed significantly across diagnosis and age, with progressively worse performance across degrees of impairment. Among the participants who were cognitively normal or had subjective cognitive concerns, poorer than expected performance on the POEM test (based on the same individual's performance on the OPID and odor discrimination tests) was associated with higher frequencies of the APOE ε4 allele, thinner entorhinal cortices, and worse longitudinal trajectory of Logical Memory scores. Interpretation: Selective impairment of episodic memory of odor percepts, relative to identification and discrimination of odor percepts revealed by this novel POEM battery, is associated with biomarkers of AD in a well-characterized pre-MCI population. These affordable, noninvasive olfactory tests offer potential to identify clinically normal individuals who have greater likelihood of future cognitive decline. Ann Neurol 2016;80:846–857.Maternal dementia age at onset in relation to amyloid burden in non-demented elderly offspring
AbstractMaye, J. E., Betensky, R. A., Gidicsin, C. M., Locascio, J., Becker, J. A., Pepin, L., Carmasin, J., Rentz, D. M., Marshall, G. A., Blacker, D., Sperling, R. A., & Johnson, K. A. (n.d.).Publication year
2016Journal title
Neurobiology of AgingVolume
40Page(s)
61-67AbstractFamily history (FH) of dementia is a major risk factor for Alzheimer's disease, particularly when the FH is maternal and when the age of dementia onset (AO) is younger. This study tested whether brain amyloid-beta deposition, measured in vivo with 11C-Pittsburgh compound B (PiB), was associated with parental dementia and/or younger parental AO. Detailed FH and positron emission tomography (PiB) data were acquired in 147 nondemented aging individuals (mean age 75 ± 8). No participant had both positive maternal and paternal FH. A series of analyses revealed that those with maternal, but not paternal, FH had greater levels of PiB retention in a global cortical region than those without FH. PiB retention in maternal FH was not significantly greater than paternal FH. Younger maternal dementia AO was related to greater PiB retention in offspring, whereas younger paternal dementia AO was not. Overall, results suggest that not only is amyloid-beta burden greater in individuals with maternal FH, but also that the burden is greater in association with younger maternal AO.Multiple imputation of a randomly censored covariate improves logistic regression analysis
AbstractAtem, F. D., Qian, J., Maye, J. E., Johnson, K. A., & Betensky, R. A. (n.d.).Publication year
2016Journal title
Journal of Applied StatisticsVolume
43Issue
15Page(s)
2886-2896AbstractRandomly censored covariates arise frequently in epidemiologic studies. The most commonly used methods, including complete case and single imputation or substitution, suffer from inefficiency and bias. They make strong parametric assumptions or they consider limit of detection censoring only. We employ multiple imputation, in conjunction with semi-parametric modeling of the censored covariate, to overcome these shortcomings and to facilitate robust estimation. We develop a multiple imputation approach for randomly censored covariates within the framework of a logistic regression model. We use the non-parametric estimate of the covariate distribution or the semi-parametric Cox model estimate in the presence of additional covariates in the model. We evaluate this procedure in simulations, and compare its operating characteristics to those from the complete case analysis and a survival regression approach. We apply the procedures to an Alzheimer's study of the association between amyloid positivity and maternal age of onset of dementia. Multiple imputation achieves lower standard errors and higher power than the complete case approach under heavy and moderate censoring and is comparable under light censoring. The survival regression approach achieves the highest power among all procedures, but does not produce interpretable estimates of association. Multiple imputation offers a favorable alternative to complete case analysis and ad hoc substitution methods in the presence of randomly censored covariates within the framework of logistic regression.Optimization of Signal Decomposition Matched Filtering (SDMF) for Improved Detection of Copy-Number Variations
AbstractStamoulis, C., & Betensky, R. A. (n.d.).Publication year
2016Journal title
IEEE/ACM Transactions on Computational Biology and BioinformaticsVolume
13Issue
3Page(s)
584-591AbstractWe aim to improve the performance of the previously proposed signal decomposition matched filtering (SDMF) method [26] for the detection of copy-number variations (CNV) in the human genome. Through simulations, we show that the modified SDMF is robust even at high noise levels and outperforms the original SDMF method, which indirectly depends on CNV frequency. Simulations are also used to develop a systematic approach for selecting relevant parameter thresholds in order to optimize sensitivity, specificity and computational efficiency. We apply the modified method to array CGH data from normal samples in the cancer genome atlas (TCGA) and compare detected CNVs to those estimated using circular binary segmentation (CBS) [19] , a hidden Markov model (HMM)-based approach [11] and a subset of CNVs in the Database of Genomic Variants. We show that a substantial number of previously identified CNVs are detected by the optimized SDMF, which also outperforms the other two methods.Plaque-associated local toxicity increases over the clinical course of Alzheimer disease
AbstractSerrano-Pozo, A., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (n.d.).Publication year
2016Journal title
American Journal of PathologyVolume
186Issue
2Page(s)
375-384AbstractAmyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312+ dystrophic neurites, GFAP+ reactive astrocytes, and IBA1+ and CD68+ activated microglia in randomly selected dense-core (Thioflavin-S+) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques. Dystrophic neurites (Kendall τ = 0.34, P = 0.001), reactive astrocytes (Kendall τ = 0.30, P = 0.003), and CD68+ (Kendall τ = 0.48, P < 0.0001), but not IBA1 microglia (Kendall τ = 0.045, P = 0.655), exhibited a significant positive correlation with symptom duration. When excluding control subjects, only the positive association between CD68+ microglia and symptom duration remained significant (Kendall τ = 0.39, P = 0.0003). The presence of the APOEε4 allele did not affect these results. We conclude that plaques exert an increasing toxicity in the surrounding neuropil over the clinical course of AD, thereby potentially contributing to cognitive decline.Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV
AbstractGrishchuk, Y., Stember, K. G., Matsunaga, A., Olivares, A. M., Cruz, N. M., King, V. E., Humphrey, D. M., Wang, S. L., Muzikansky, A., Betensky, R. A., Thoreson, W. B., Haider, N., & Slaugenhaupt, S. A. (n.d.).Publication year
2016Journal title
American Journal of PathologyVolume
186Issue
1Page(s)
199-209AbstractMucolipidosis IV is a debilitating developmental lysosomal storage disorder characterized by severe neuromotor retardation and progressive loss of vision, leading to blindness by the second decade of life. Mucolipidosis IV is caused by loss-of-function mutations in the MCOLN1 gene, which encodes the transient receptor potential channel protein mucolipin-1. Ophthalmic pathology in patients includes corneal haze and progressive retinal and optic nerve atrophy. Herein, we report ocular pathology in Mcoln1-/- mouse, a good phenotypic model of the disease. Early, but non-progressive, thinning of the photoreceptor layer, reduced levels of rhodopsin, disrupted rod outer segments, and widespread accumulation of the typical storage inclusion bodies were the major histological findings in the Mcoln1-/- retina. Electroretinograms showed significantly decreased functional response (scotopic a- and b-wave amplitudes) in the Mcoln1-/- mice. At the ultrastructural level, we observed formation of axonal spheroids and decreased density of axons in the optic nerve of the aged (6-month-old) Mcoln1-/- mice, which indicates progressive axonal degeneration. Our data suggest that mucolipin-1 plays a role in postnatal development of photoreceptors and provides a set of outcome measures that can be used for ocular therapy development for mucolipidosis IV.Tau positron emission tomographic imaging in aging and early Alzheimer disease
AbstractJohnson, K. A., Schultz, A., Betensky, R. A., Becker, J. A., Sepulcre, J., Rentz, D., Mormino, E., Chhatwal, J., Amariglio, R., Papp, K., Marshall, G., Albers, M., Mauro, S., Pepin, L., Alverio, J., Judge, K., Philiossaint, M., Shoup, T., Yokell, D., … Sperling, R. (n.d.).Publication year
2016Journal title
Annals of NeurologyVolume
79Issue
1Page(s)
110-119AbstractObjective Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease-modifying therapies. Methods We acquired tau positron emission tomography (PET) using 18F T807 (AV1451), and amyloid-β PET using 11C Pittsburgh compound B (PiB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia. Results We found abnormally high cortical 18F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical 18F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal 18F T807 than with mean cortical 11C PIB. Regional 18F T807 was correlated with mean cortical 11C PiB among both impaired and control subjects. Interpretation These findings suggest that 18F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment.Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease continuum
AbstractSerrano-Pozo, A., Qian, J., Muzikansky, A., Monsell, S. E., Montine, T. J., Frosch, M. P., Betensky, R. A., & Hyman, B. T. (n.d.).Publication year
2016Journal title
Journal of Neuropathology and Experimental NeurologyVolume
75Issue
6Page(s)
516-526AbstractThe 2012 neuropathological criteria for the diagnosis of Alzheimer disease (AD) summarize the extent of AD neuropathological change with an ABC score, which is a composite of the Thal stage of amyloid deposition (A), the Braak stage of neurofibrillary tangles (NFTs) (B), and the CERAD neuritic plaque score (C). NFTs and neuritic plaques are well-established contributors to cognitive impairment, but whether the Thal amyloid stage independently predicts antemortem cognition remains unknown. We used the National Alzheimer's Coordinating Center autopsy data set to build adjacent-categories logit regression models with CDR-SOB and Mini-Mental State Examination (MMSE) scores as cognitive outcome variables. Increasing CERAD scores were independently associated with higher CDR-SOB scores, whereas increasing Braak NFT stages predicted both higher CDR-SOB and lower MMSE scores. Increasing Thal amyloid stages were not significantly independently associated with either outcome measure. Increasing ABC scores predicted higher CDR-SOB and lower MMSE scores. These results raise the possibility that Thal amyloid stages do not substantially contribute to predicting antemortem cognition compared to CERAD neuritic plaque scores and Braak NFT stages, and suggest that the diffuse amyloid deposits participating in the assignment of Thal amyloid stages are neutral with respect to clinically detectable cognitive and functional changes.Thioesterase superfamily member 1 suppresses cold thermogenesis by limiting the oxidation of lipid droplet-derived fatty acids in brown adipose tissue
AbstractOkada, K., LeClair, K. B., Zhang, Y., Li, Y., Ozdemir, C., Krisko, T. I., Hagen, S. J., Betensky, R. A., Banks, A. S., & Cohen, D. E. (n.d.).Publication year
2016Journal title
Molecular MetabolismVolume
5Issue
5Page(s)
340-351AbstractObjective: Non-shivering thermogenesis in brown adipose tissue (BAT) plays a central role in energy homeostasis. Thioesterase superfamily member 1 (Them1), a BAT-enriched long chain fatty acyl-CoA thioesterase, is upregulated by cold and downregulated by warm ambient temperatures. Them1-/- mice exhibit increased energy expenditure and resistance to diet-induced obesity and diabetes, but the mechanistic contribution of Them1 to the regulation of cold thermogenesis remains unknown. Methods: Them1-/- and Them1+/+ mice were subjected to continuous metabolic monitoring to quantify the effects of ambient temperatures ranging from thermoneutrality (30 °C) to cold (4 °C) on energy expenditure, core body temperature, physical activity and food intake. The effects of Them1 expression on O2 consumption rates, thermogenic gene expression and lipolytic protein activation were determined ex vivo in BAT and in primary brown adipocytes. Results: Them1 suppressed thermogenesis in mice even in the setting of ongoing cold exposure. Without affecting thermogenic gene transcription, Them1 reduced O2 consumption rates in both isolated BAT and primary brown adipocytes. This was attributable to decreased mitochondrial oxidation of endogenous but not exogenous fatty acids. Conclusions: These results show that Them1 may act as a break on uncontrolled heat production and limit the extent of energy expenditure. Pharmacologic inhibition of Them1 could provide a targeted strategy for the management of metabolic disorders via activation of brown fat.