Rebecca A Betensky

Chair of the Department of Biostatistics

Professor of Biostatistics

Professional overview

Prior to NYU, Dr. Betensky was Professor of Biostatistics at the Harvard T.H. Chan School of Public Health. She was director of the Harvard Catalyst (Clinical and Translational Science Award) Biostatistics Program; director of the Data and Statistics Core for the Massachusetts Alzheimer’s Disease Research Center; and director of the Biostatistics Neurology Core at Massachusetts General Hospital. Previously, she was the Biostatistics Program Leader for the Dana-Farber/Harvard Cancer Center.

Dr. Betensky’s research focuses on methods for the analysis of censored and truncated outcomes and covariates, which frequently arise from the subsampling of cohort studies. She has a long-time interest in clinical trials, and has written on the evaluation of biomarkers and the use and interpretation of p-values. She has collaborated extensively in studies in neurologic diseases, and serves as statistical editor for Annals of Neurology.

Dr. Betensky was awarded, and directed for 15 years, an NIH T32 training program in neurostatistics and neuroepidemiology for pre- and post-doctoral students in biostatistics and epidemiology and for clinician-scientists. She previously directed Harvard’s Biostatistics programs to promote and support diversity at all levels in the field of quantitative public health. She was also a member of the BMRD Study Section for review of NIH statistical methodology grants; on committees for the Institute of Medicine; and a co-chair of the technical advisory committee for the scientific registry of transplant recipients.

Dr. Betensky an elected Fellow of the American Statistical Association and of the International Statistical Institute, and is a past recipient of the Spiegelman Award from the American Public Health Association. She currently serves as a member of the Board of Scientific Counselors for Clinical Science and Epidemiology at the National Cancer Institute.

Education

AB, Mathematics, Harvard University, Cambridge, MA

PhD, Statistics, Stanford University, Stanford, CA

Areas of research and study

Biology

Biostatistics

Neuroepidemiology

Neurology

Neurostatistics

Translational science

Publications

Publications

Remote supervision of IV-tPA for acute ischemic stroke by telemedicine or telephone before transfer to a regional stroke center is feasible and safe

Pervez, M. A., Silva, G., Masrur, S., Betensky, R., Furie, K. L., Hidalgo, R., Lima, F., Rosenthal, E. S., Rost, N., Viswanathan, A., & Schwamm, L. H. (n.d.).

Publication year

2010

Journal title

Stroke

Volume

41

Issue

1

Page(s)

e18-e24

10.1161/STROKEAHA.109.560169

Abstract

Abstract

BACKGROUND AND PURPOSE-: Because of a shortage of stroke specialists, many outlying or "spoke" hospitals initiate intravenous (IV) thrombolysis using telemedicine or telephone consultation before transferring patients to a regional stroke center (RSC) hub. We analyzed complications and outcomes of patients treated with IV tissue plasminogen activator (tPA) using the "drip and ship" approach compared to those treated directly at the RSC. METHODS-: A retrospective review of our Get With the Guidelines Stroke (GWTG-Stroke) database from 01/2003 to 03/2008 identified 296 patients who received IV tPA within 3 hours of symptom onset without catheter-based reperfusion. GWTG-Stroke definitions for symptomatic intracranial (sICH), systemic hemorrhage, discharge functional status, and destination were applied. Follow-up modified Rankin Score was recorded when available. RESULTS-: Of 296 patients, 181 (61.1%) had tPA infusion started at an outside spoke hospital (OSH) and 115 (38.9%) at the RSC hub. OSH patients were younger with fewer severe strokes than RSC patients. Patients treated based on telestroke were more frequently octogenarians than patients treated based on a telephone consult. Mortality, sICH, and functional outcomes were not different between OSH versus RSC and telephone versus telestroke patients. Among survivors, mean length of stay was shorter for OSH patients but discharge status was similar and 75% of patients walked independently at discharge. CONCLUSIONS-: Outcomes in OSH "drip and ship" patients treated in a hub-and-spoke network were comparable to those treated directly at an RSC. These data suggest that "drip and ship" is a safe and effective method to shorten time to treatment with IV tPA.

Reply to Sabanés Bové and Held's "Comment on Cai and Betensky (2003), On the Poisson Approximation for Hazard Regression"

Cai, T., & Betensky, R. (n.d.).

Publication year

2013

Journal title

Biometrics

Volume

69

Issue

3

Page(s)

796

10.1111/biom.12087

Abstract

Abstract

~

Reply to Tendler et al

Betensky, R., Taylor, J. J. J., Newberger, N. G., Stern, A. P., Phillips, A., Feifel, D., Betensky, R. A., & Press, D. Z. (n.d.).

Publication year

2021

Journal title

Brain stimulation

Volume

14

Issue

5

Page(s)

1216-1217

Abstract

Abstract

~

Research participant compensation : A matter of statistical inference as well as ethics

Swanson, D. M., & Betensky, R. (n.d.).

Publication year

2015

Journal title

Contemporary Clinical Trials

Volume

45

Page(s)

265-269

10.1016/j.cct.2015.08.014

Abstract

Abstract

The ethics of compensation of research subjects for participation in clinical trials has been debated for years. One ethical issue of concern is variation among subjects in the level of compensation for identical treatments. Surprisingly, the impact of variation on the statistical inferences made from trial results has not been examined. We seek to identify how variation in compensation may influence any existing dependent censoring in clinical trials, thereby also influencing inference about the survival curve, hazard ratio, or other measures of treatment efficacy. In simulation studies, we consider a model for how compensation structure may influence the censoring model. Under existing dependent censoring, we estimate survival curves under different compensation structures and observe how these structures induce variability in the estimates. We show through this model that if the compensation structure affects the censoring model and dependent censoring is present, then variation in that structure induces variation in the estimates and affects the accuracy of estimation and inference on treatment efficacy. From the perspectives of both ethics and statistical inference, standardization and transparency in the compensation of participants in clinical trials are warranted.

Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV

Grishchuk, Y., Stember, K. G., Matsunaga, A., Olivares, A. M., Cruz, N. M., King, V. E., Humphrey, D. M., Wang, S. L., Muzikansky, A., Betensky, R., Thoreson, W. B., Haider, N., & Slaugenhaupt, S. A. (n.d.).

Publication year

2016

Journal title

American Journal of Pathology

Volume

186

Issue

1

Page(s)

199-209

10.1016/j.ajpath.2015.09.017

Abstract

Abstract

Mucolipidosis 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.

Risk factors for perineal wound complications following abdominoperineal resection

Christian, C. K., Kwaan, M. R., Betensky, R., Breen, E. M., Zinner, M. J., & Bleday, R. (n.d.).

Publication year

2005

Journal title

Diseases of the Colon and Rectum

Volume

48

Issue

1

Page(s)

43-48

10.1007/s10350-004-0855-x

Abstract

Abstract

PURPOSE: Perineal wound complications are common following abdominoperineal resection. This study investigates the factors contributing to these complications. Methods: Patients undergoing abdominoperineal resection at our institution from June 1997 to May 2003 were reviewed. Significant predictors associated with minor (separation 2 cm of separation, reoperation required, or readmission) wound complications were ascertained. Results: Of 153 patients, there were 22 major (14 percent) and 32 minor (24 percent) wound complications. Patients with anal cancer had a higher rate of major complications than those with rectal cancer or inflammatory bowel disease. Minor wound complications were more common in patients with anal cancer and inflammatory bowel disease than those with rectal cancer. Factors associated with a higher rate of major wound complications included flap closure, tumor size, body mass index, diabetes, and indication for the procedure. When the subset of patients with rectal cancer was considered, higher rates of major wounds were associated with increased body mass index, diabetes, and stage. Minor complications were associated with a two-team approach and increasing body mass index. Conclusions: This is currently the largest review of perineal wound complications following abdominoperineal resection. Patients with anal cancer and inflammatory bowel disease were at higher risk for perineal wound complications than those with rectal cancer. Preoperative radiation and primary closure were not associated with increased complications following abdominoperineal resection for rectal cancer.

Sample size re-estimation in cluster randomization trials

Lake, S., Kammann, E., Klar, N., & Betensky, R. (n.d.).

Publication year

2002

Journal title

Statistics in Medicine

Volume

21

Issue

10

Page(s)

1337-1350

10.1002/sim.1121

Abstract

Abstract

Cluster randomization trials in which families are the unit of allocation are commonly adopted for the evaluation of disease prevention interventions. Sample size estimation for cluster randomization trials depends on parameters that quantify the variability within and between clusters and the variability in cluster size. Accurate advance estimates of these nuisance parameters may be difficult to obtain and misspecification may lead to an underpowered study. Since families are typically recruited over time, we propose using a portion of the data to estimate the nuisance parameters and to re-estimate sample size based on the estimates. This extends the standard internal pilot study methods to the setting of cluster randomization trials. The effect of this design on the power, significance level and sample size is analysed via simulation and is shown to provide a flexible and practical approach to cluster randomization trials.

Seizure risk with repetitive TMS : Survey results from over a half-million treatment sessions

Taylor, J. J., Newberger, N. G., Stern, A. P., Phillips, A., Feifel, D., Betensky, R., & Press, D. Z. (n.d.).

Publication year

2021

Journal title

Brain Stimulation

Volume

14

Issue

4

Page(s)

965-973

10.1016/j.brs.2021.05.012

Abstract

Abstract

Background: Seizures are rare during repetitive transcranial magnetic stimulation (rTMS) treatment, but estimating risk is difficult because of study heterogeneity and sampling limitations. Moreover, there are few studies comparing rates between device manufacturers. Objective: The objective of this study was to calculate rTMS seizure rates across various FDA-cleared devices in naturalistic clinical settings. Methods: In July and August 2018, approximately 500 members of the Clinical TMS Society (CTMSS) were electronically surveyed about seizures in their practices. Seizures were distinguished from non-seizures by a remote semi-structured interview with a Board-certified neurologist and Co-Chair of the CTMSS Standards Committee. Exact Poisson calculations were used to estimate seizure rates and confidence intervals across the four most widely used manufacturers. Results: The survey was completed by 134 members, with 9 responses excluded because of data inconsistencies. In total, 18 seizures were reported in 586,656 sessions and 25,526 patients across all device manufacturers. The overall seizure rate was 0.31 (95% CI: 0.18, 0.48) per 10,000 sessions, and 0.71 (95% CI: 0.42, 1.11) per 1000 patients. The Brainsway H-coil seizure rate of 5.56 per 1000 patients (95% CI: 2.77,9.95) was significantly higher (p < 0.001) than the three most widely used figure- 8 coil devices’ combined seizure rate of 0.14 per 1000 patients (95% CI: 0.01, 0.51). Conclusion: The absolute risk of a seizure with rTMS is low, but generic Brainsway H-coil treatment appears to be associated with a higher relative risk than generic figure- 8 coil treatment. Well-designed prospective studies are warranted to further investigate this risk.

Sequential analysis of censored survival data from three treatment groups

Betensky, R. (n.d.).

Publication year

1997

Journal title

Biometrics

Volume

53

Issue

3

Page(s)

807-822

10.2307/2533544

Abstract

Abstract

In this paper, we propose a simple means of designing and analyzing a sequential procedure for comparing survival data from three treatments with the goal of eventually identifYing the best treatment. Our procedure consists of the concatenation of two sequential tests, as is suggested by Siegmund (1993, Annals of Statistics 21, 464-483) for instantaneous normal responses. The first sequential test is a global test that attempts to detect an overall treatment effect. If one is found, the least promising treatment is eliminated and a second sequential test attempts to identify the better of the two remaining treatments. Although there are three different information time scales to consider corresponding to each pairwise comparison, we show that under certain conditions they may be approximated by a single time scale. This enables us to gain insight into the problem of censored survival data from the more easily understood case of instantaneous normal data. Also, it eliminates the need for intensive computations and simulations for the design and analysis of the procedure.

Serum levels of 25-hydroxyvitamin D at diagnosis are not associated with overall survival in esophageal adenocarcinoma

Loehrer, E., Betensky, R., Giovannucci, E., Su, L., Shafer, A., Hollis, B. W., & Christiani, D. C. (n.d.).

Publication year

2019

Journal title

Cancer Epidemiology Biomarkers and Prevention

Volume

28

Issue

8

Page(s)

1379-1387

10.1158/1055-9965.EPI-18-1190

Abstract

Abstract

Background: Higher levels of circulating 25-hydroxyvitamin D [25(OH)D] are associated with longer survival in several cancers, but the results have differed across cancer sites. The association between serum 25(OH)D levels and overall survival (OS) time in esophageal adenocarcinoma remains unclear. Methods: We utilized serum samples from 476 patients with primary esophageal adenocarcinoma, recruited from Massachusetts General Hospital (Boston, MA) between 1999 and 2015. We used log-rank tests to test the difference in survival curves across quartiles of 25(OH)D levels and extended Cox modeling to estimate adjusted HRs. We tested for interactions between clinical stage or BMI on the association between 25(OH)D and OS. We additionally performed sensitivity analyses to determine whether race or timing of blood draw (relative to treatment) affected these results. Results: We found no evidence that survival differed across quartiles of 25(OH)D (log rank P = 0.48). Adjusting for confounders, we found no evidence that the hazard of death among the highest quartile of 25(OH)D (quartile 1) differed from any other quartile [quartile 2 HR = 0.90, 95% confidence interval (CI), 0.67-1.23; quartile 3 HR = 1.03, 95% CI, 0.76- 1.38; quartile 4 (lowest) HR = 0.98, 95% CI, 0.72-1.33]. Sensitivity analyses yielded consistent results when accounting for race or time between diagnosis and blood draw. Moreover, we did not find evidence of interaction between 25(OH)D and clinical stage or BMI on OS. Conclusions: Serum level of 25(OH)D near time of diagnosis was not associated with OS in patients with esophageal adenocarcinoma. Impact: Screening 25(OH)D levels among patients with esophageal adenocarcinoma at diagnosis is not clinically relevant to their cancer prognosis based on present evidence.

Sex and Race Differences in the Evaluation and Treatment of Young Adults Presenting to the Emergency Department With Chest Pain

Betensky, R., Banco, D., Chang, J., Talmor, N., Wadhera, P., Mukhopadhyay, A., Lu, X., Dong, S., Lu, Y., Betensky, R. A., Blecker, S., Safdar, B., & Reynolds, H. R. (n.d.).

Publication year

2022

Journal title

Journal of the American Heart Association

Volume

11

Issue

10

Page(s)

e024199

Abstract

Abstract

Background Acute myocardial infarctions are increasingly common among young adults. We investigated sex and racial differences in the evaluation of chest pain (CP) among young adults presenting to the emergency department. Methods and Results Emergency department visits for adults aged 18 to 55 years presenting with CP were identified in the National Hospital Ambulatory Medical Care Survey 2014 to 2018, which uses stratified sampling to produce national estimates. We evaluated associations between sex, race, and CP management before and after multivariable adjustment. We identified 4152 records representing 29 730 145 visits for CP among young adults. Women were less likely than men to be triaged as emergent (19.1% versus 23.3%, respectively,

Sex and Race Differences in the Evaluation and Treatment of Young Adults Presenting to the Emergency Department With Chest Pain

Banco, D., Chang, J., Talmor, N., Wadhera, P., Mukhopadhyay, A., Lu, X., Dong, S., Lu, Y., Betensky, R., Blecker, S., Safdar, B., & Reynolds, H. R. (n.d.).

Publication year

2022

Journal title

Journal of the American Heart Association

Volume

11

Issue

10

10.1161/JAHA.121.024199

Abstract

Abstract

BACKGROUND: Acute myocardial infarctions are increasingly common among young adults. We investigated sex and racial differences in the evaluation of chest pain (CP) among young adults presenting to the emergency department. METHODS AND RESULTS: Emergency department visits for adults aged 18 to 55 years presenting with CP were identified in the National Hospital Ambulatory Medical Care Survey 2014 to 2018, which uses stratified sampling to produce national estimates. We evaluated associations between sex, race, and CP management before and after multivariable adjustment. We identified 4152 records representing 29 730 145 visits for CP among young adults. Women were less likely than men to be triaged as emergent (19.1% versus 23.3%, respectively, P

Shipment impairs lymphocyte proliferative responses to microbial antigens

Betensky, R., Betensky, R. A., Connick, E., Devers, J., Landay, A. L., Nokta, M., Plaeger, S., Rosenblatt, H., Schmitz, J. L., Valentine, F., Wara, D., Weinberg, A., & Lederman, H. M. (n.d.).

Publication year

2000

Journal title

Clinical and Diagnostic Laboratory Immunology

Volume

7

Issue

5

Page(s)

759-763

10.1128/CDLI.7.5.759-763.2000

Abstract

Abstract

Lymphocyte proliferation assays (LPAs) are widely used to assess T-lymphocyte function of patients with human immunodeficiency virus infection and other primary and secondary immunodeficiency disorders. Since these assays require expertise not readily available at all clinical sites, specimens may be shipped to central labs for testing. We conducted a large multicenter study to evaluate the effects of shipping on assay performance and found significant loss of LPA activity. This may lead to erroneous results for individual subjects and introduce bias into multicenter trials.

Simple approximations for the maximal transmission/disequilibrium test with a multi-allelic marker

Betensky, R., Betensky, R. A., & Rabinowitz, D. (n.d.).

Publication year

2000

Journal title

Annals of Human Genetics

Volume

64

Issue

6

Page(s)

567-574

10.1017/S0003480000008356

Abstract

Abstract

Spielman et al. (1993) popularized the transmission/disequilibrium test (TDT) to test for linkage between disease and marker loci that show a population association. Several authors have proposed extensions to the TDT for multi-allelic markers. Many of these approaches exhibit a 'swamping' effect in which a marker with a strong effect is not detected by a global test that includes many markers with no effect. To avoid this effect, Schaid (1996) proposed using the maximum of the bi-allelic TDT statistics computed for each allele versus all others combined. The maximal TDT statistic, however, no longer follows a chi-square distribution. Here, a refinement to Bonferroni's correction for multiple testing provided by Worsley (1982) based on maximal spanning trees is applied to calculate accurate upper bounds for the type I error and p-values for the maximal TDT. In addition, an accurate lower Bonferroni bound is applied to calculate power. This approach does not require any simulation-based analysis and is less conservative than the standard Bonferroni correction. The bounds are given for both the exact probability calculations and for those based on the normal approximation. The results are assessed through simulations.

Simulation of New York City's Ventilator Allocation Guideline During the Spring 2020 COVID-19 Surge

Betensky, R., Walsh, B. C., Zhu, J., Feng, Y., Berkowitz, K. A., Betensky, R. A., Nunnally, M. E., & Pradhan, D. R. (n.d.).

Publication year

2023

Journal title

JAMA network open

Volume

6

Issue

10

Page(s)

e2336736

Abstract

Abstract

The spring 2020 surge of COVID-19 unprecedentedly strained ventilator supply in New York City, with many hospitals nearly exhausting available ventilators and subsequently seriously considering enacting crisis standards of care and implementing New York State Ventilator Allocation Guidelines (NYVAG). However, there is little evidence as to how NYVAG would perform if implemented.

Simultaneous confidence intervals based on the percentile bootstrap approach

Mandel, M., & Betensky, R. (n.d.).

Publication year

2008

Journal title

Computational Statistics and Data Analysis

Volume

52

Issue

4

Page(s)

2158-2165

10.1016/j.csda.2007.07.005

Abstract

Abstract

This note concerns the construction of bootstrap simultaneous confidence intervals (SCI) for m parameters. Given B bootstrap samples, we suggest an algorithm with complexity of O (mB log (B)). We apply our algorithm to construct a confidence region for time dependent probabilities of progression in multiple sclerosis and for coefficients in a logistic regression analysis. Alternative normal based simultaneous confidence intervals are presented and compared to the bootstrap intervals.

Social Determinants of Health Predict Brain MRI Severity in Pediatric Onset MultipleSclerosis

Ross, R., O’Neill, K. A., Betensky, R., Billiet, T., Kenney, R., Lovett, J. T., Maletic-Savatic, M., Meeks, H. D., Sosa, A., Waltz, M., & Krupp, L. (n.d.).

Abstract

Abstract

~

Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain

Arbel-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., Hyman, B. T., & Bacskai, B. J. (n.d.).

Publication year

2017

Journal title

Molecular Neurodegeneration

Volume

12

Issue

1

10.1186/s13024-017-0169-9

Abstract

Abstract

Background: 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.

Somatic mitochondrial DNA mutations in early Parkinson and incidental lewy body disease

Lin, M. T., Cantuti-Castelvetri, I., Zheng, K., Jackson, K. E., Tan, Y. B., Arzberger, T., Lees, A. J., Betensky, R., Beal, M. F., & Simon, D. K. (n.d.).

Publication year

2012

Journal title

Annals of Neurology

Volume

71

Issue

6

Page(s)

850-854

10.1002/ana.23568

Abstract

Abstract

Somatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra neurons are significantly elevated in this group of early PD and ILBD cases.

Somatic mitochondrial DNA mutations in single neurons and glia

Cantuti-Castelvetri, I., Lin, M. T., Zheng, K., Keller-McGandy, C. E., Betensky, R., Johns, D. R., Beal, M. F., Standaert, D. G., & Simon, D. K. (n.d.).

Publication year

2005

Journal title

Neurobiology of Aging

Volume

26

Issue

10

Page(s)

1343-1355

10.1016/j.neurobiolaging.2004.11.008

Abstract

Abstract

Somatic mitochondrial DNA (mtDNA) point mutations reach high levels in the brain. However, the cell types that accumulate mutations and the patterns of mutations within individual cells are not known. We have quantified somatic mtDNA mutations in 28 single neurons and in 18 single glia from post-mortem human substantia nigra of six control subjects. Both neurons and glia contain mtDNA with somatic mutations. Single neurons harbor a geometric mean (95% CI) of 200.3 (152.9-262.4) somatic mtDNA point mutations per million base pairs, compared to 133.8 (97.5-184.9) for single glia (p = 0.0251). If mutations detected multiple times in the same cell are counted only once, the mean mutation level per million base pairs remains elevated in single neurons (146.9; 124.0-174.2) compared to single glia (100.5; 81.5-126.5; p = 0.009). Multiple distinct somatic point mutations are present in different cells from the same subject. Most of these mutations are individually present at low levels (less than 10-20% of mtDNA molecules), but with high aggregate mutation levels, particularly in neurons. These mutations may contribute to changes in brain function during normal aging and neurodegenerative disorders.

Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy

Rosand, J., Muzikansky, A., Kumar, A., Wisco, J. J., Smith, E. E., Betensky, R., & Greenberg, S. M. (n.d.).

Publication year

2005

Journal title

Annals of Neurology

Volume

58

Issue

3

Page(s)

459-462

10.1002/ana.20596

Abstract

Abstract

Cerebral amyloid angiopathy (CAA) is a common cause of symptomatic intracerebral hemorrhage (ICH), as well as small asymptomatic hemorrhage in the elderly. We used gradient-echo MRI to analyze spatial distribution of 321 hemorrhages in 59 patients with probable CAA-related ICH. Hemorrhagic lesions were found preferentially in the temporal (ratio of actual to expected hemorrhages = 1.37) and occipital lobes (ratio = 1.45, p < 0.0001). Within individuals, hemorrhages tended to cluster, regardless of lobe (p < 0.0001). Among subjects followed prospectively for recurrence, clustering of new symptomatic and asymptomatic hemorrhages was observed. These data suggest that regional differences within the brain play a role in the development of CAA-related hemorrhage.

Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy

Dierksen, G. A., Skehan, M. E., Khan, M. A., Jeng, J., Nandigam, R. N., Becker, J. A., Kumar, A., Neal, K. L., Betensky, R., Frosch, M. P., Rosand, J., Johnson, K. A., Viswanathan, A., Salat, D. H., & Greenberg, S. M. (n.d.).

Publication year

2010

Journal title

Annals of Neurology

Volume

68

Issue

4

Page(s)

545-548

10.1002/ana.22099

Abstract

Abstract

Advanced cerebrovascular β-amyloid deposition (cerebral amyloid angiopathy, CAA) is associated with cerebral microbleeds, but the precise relationship between CAA burden and microbleeds is undefined. We used T2*-weighted magnetic resonance imaging (MRI) and noninvasive amyloid imaging with Pittsburgh Compound B (PiB) to analyze the spatial relationship between CAA and microbleeds. On coregistered positron emission tomography (PET) and MRI images, PiB retention was increased at microbleed sites compared to simulated control lesions (p = 0.002) and declined with increasing distance from the microbleed (p < 0.0001). These findings indicate that microbleeds occur preferentially in local regions of concentrated amyloid and support therapeutic strategies aimed at reducing vascular amyloid deposition.

Stable size distribution of amyloid plaques over the course of alzheimer disease

Serrano-Pozo, A., Mielke, M. L., Muzitansky, A., Gómez-Isla, T., Growdon, J. H., Bacskai, B. J., Betensky, R., Frosch, M. P., & Hyman, B. T. (n.d.).

Publication year

2012

Journal title

Journal of Neuropathology and Experimental Neurology

Volume

71

Issue

8

Page(s)

694-701

10.1097/NEN.0b013e31825e77de

Abstract

Abstract

Amyloid β plaques are a key pathologic feature of Alzheimer disease (AD), but whether plaque sizes increase or stabilize over the course of AD is unknown. We measured the size distribution of total immunoreactive (10D5-positive) and dense-core (Thioflavin S-positive) plaques in the temporal neocortex of a large group of subjects with AD and age-matched plaque-bearing subjects without dementia to test the hypothesis that amyloid plaques continue to grow along with the progression of the disease. The size of amyloid β (10D5)-positive plaques did not differ between groups, whereas dense-core plaques from the group with AD were slightly larger than those from the group without dementia (∼25%-30%, p = 0.01). Within the group with AD, dense-core plaque size did not independently correlate with duration of clinical disease (from 4 to 21 years, p = 0.68), whereas 10D5-positive plaque size correlated negatively with disease duration (p = 0.01). By contrast, an earlier age of symptom onset strongly predicted a larger postmortem plaque size; this effect was independent of disease duration and the presence of the APOE[Latin Small Letter Open E]4 allele (p = 0.0001). We conclude that plaques vary in size among patients, with larger size distributions correlating with an earlier age of onset, but plaques do not substantially increase in size over the clinical course of the disease.

Statistical considerations for immunohistochemistry panel development after expression profiling of human cancers

Betensky, R., Nutt, C. L., Batchelor, T. T., & Louis, D. N. (n.d.).

Publication year

2005

Journal title

Journal of Molecular Diagnostics

Volume

7

Issue

2

Page(s)

276-282

10.1016/S1525-1578(10)60555-7

Abstract

Abstract

In recent years there have been a number of microarray expression studies in which different types of tumors were classified by identifying a panel of differentially expressed genes. Immunohistochemistry is a practical and robust method for extending gene expression data to common pathological specimens with the advantage of being applicable to paraffin-embedded tissues. However, the number of assays required for successful immunohistochemical classification remains unclear. We propose a simulation-based method for assessing sample size for an immunohistochemistry investigation after a promising gene expression study of human tumors. The goals of such an immunohistochemistry study would be to develop and validate a marker panel that yields improved prognostic classification of cancer patients. We demonstrate how the preliminary gene expression data, coupled with certain realistic assumptions, can be used to estimate the number of immunohistochemical assays required for development These assumptions are more tenable than alternative assumptions that would be required for crude analytic sample size calculations and that may yield underpowered and inefficient studies. We applied our methods to the design of an immunohistochemistry study for glioma classification and estimated the number of assays required to ensure satisfactory technical and prognostic validation. Simulation approaches for computing power and sample size that are based on existing gene expression data provide a powerful tool for efficient design of follow-up genomic studies.

Supervised Bayesian latent class models for high-dimensional data

Desantis, S. M., Andrés Houseman, E., Coull, B. A., Nutt, C. L., & Betensky, R. (n.d.).

Publication year

2012

Journal title

Statistics in Medicine

Volume

31

Issue

13

Page(s)

1342-1360

10.1002/sim.4448

Abstract

Abstract

High-grade gliomas are the most common primary brain tumors in adults and are typically diagnosed using histopathology. However, these diagnostic categories are highly heterogeneous and do not always correlate well with survival. In an attempt to refine these diagnoses, we make several immunohistochemical measurements of YKL-40, a gene previously shown to be differentially expressed between diagnostic groups. We propose two latent class models for classification and variable selection in the presence of high-dimensional binary data, fit by using Bayesian Markov chain Monte Carlo techniques. Penalization and model selection are incorporated in this setting via prior distributions on the unknown parameters. The methods provide valid parameter estimates under conditions in which standard supervised latent class models do not, and outperform two-stage approaches to variable selection and parameter estimation in a variety of settings. We study the properties of these methods in simulations, and apply these methodologies to the glioma study for which identifiable three-class parameter estimates cannot be obtained without penalization. With penalization, the resulting latent classes correlate well with clinical tumor grade and offer additional information on survival prognosis that is not captured by clinical diagnosis alone. The inclusion of YKL-40 features also increases the precision of survival estimates. Fitting models with and without YKL-40 highlights a subgroup of patients who have glioblastoma (GBM) diagnosis but appear to have better prognosis than the typical GBM patient.