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
COVID-19 in Individuals Treated With Long-Term Hydroxychloroquine: A Propensity Score-Matched Analysis of Cicatricial Alopecia Patients
AbstractBetensky, R., Shaw, K. S., Yin, L., Shah, J. K., Sally, R. A., Svigos, K. S., Adotama, P. U., Tuan, H. H. H., Shapiro, J., Betensky, R. A., & Lo Siccoa, K. I. (n.d.).Publication year
2021Journal title
Journal of drugs in dermatology : JDDVolume
20Issue
8Page(s)
914-916AbstractEarly in the COVID-19 pandemic, anti-malarial agent hydroxychloroquine (HCQ) was touted as a potentially effective COVID-19 treatment due to its purported antiinflammatory and antiviral effects.Creatinine as the gold standard for kidney injury biomarker studies
AbstractWaikar, S. S., Betensky, R., & Bonventre, J. V. (n.d.).Publication year
2009Journal title
Nephrology Dialysis TransplantationVolume
24Issue
11Page(s)
3263-3265Abstract~Decreased hippocampal metabolism in high-amyloid mild cognitive impairment
AbstractHanseeuw, B. J., Schultz, A. P., Betensky, R., 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.Defining the Lowest Threshold for Amyloid-PET to Predict Future Cognitive Decline and Amyloid Accumulation
AbstractBetensky, R. (n.d.).Publication year
2021Journal title
NeurologyVolume
96Issue
4Page(s)
e619-e631AbstractINTRODUCTION: As clinical trials move toward earlier intervention, we sought to redefine the β-amyloid (Aβ)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future Aβ accumulation and cognitive decline in 3 independent samples of clinically normal individuals. METHODS: Sequential Aβ cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and Aβ-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356). RESULTS: Within samples, cutoffs derived from future Aβ-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15-18.5). DISCUSSION: These optimized thresholds can help to inform future research and clinical trials targeting early Aβ. Threshold convergence raises the possibility of contemporaneous early changes in Aβ and cognition. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among clinically normal individuals a specific Aβ-PET threshold is predictive of cognitive decline.Design and analysis considerations for combining data from multiple biomarker studies
AbstractSloan, A., Song, Y., Gail, M. H., Betensky, R., Rosner, B., Ziegler, R. G., Smith-Warner, S. A., & Wang, M. (n.d.).Publication year
2019Journal title
Statistics in MedicineVolume
38Issue
8Page(s)
1303-1320AbstractPooling data from multiple studies improves estimation of exposure-disease associations through increased sample size. However, biomarker exposure measurements can vary substantially across laboratories and often require calibration to a reference assay prior to pooling. We develop two statistical methods for aggregating biomarker data from multiple studies: the full calibration method and the internalized method. The full calibration method calibrates all biomarker measurements regardless of the availability of reference laboratory measurements while the internalized method calibrates only non-reference laboratory measurements. We compare the performance of these two aggregation methods to two-stage methods. Furthermore, we compare the aggregated and two-stage methods when estimating the calibration curve from controls only or from a random sample of individuals from the study cohort. Our findings include the following: (1) Under random sampling for calibration, exposure effect estimates from the internalized method have a smaller mean squared error than those from the full calibration method. (2) Under the controls-only calibration design, the full calibration method yields effect estimates with the least bias. (3) The two-stage approaches produce average effect estimates that are similar to the full calibration method under a controls only calibration design and the internalized method under a random sample calibration design. We illustrate the methods in an application evaluating the relationship between circulating vitamin D levels and stroke risk in a pooling project of cohort studies.Design and analysis of N-of-1 trials that incorporate sequential monitoring
AbstractJiang, S., Arnold, S. E., & Betensky, R. (n.d.).Abstract~Designed extension of survival studies : Application to clinical trials with unrecognized heterogeneity
AbstractLi, Y., Shih, M. C., & Betensky, R. (n.d.).Publication year
2007Journal title
Statistica SinicaVolume
17Issue
4Page(s)
1567-1589AbstractIt is well known that unrecognized heterogeneity among patients, such as is conferred by genetic subtype, can undermine the power of a randomized trial, designed under the assumption of homogeneity, to detect a truly beneficial treatment. We consider the conditional power approach to allow for recovery of power under unexplained heterogeneity. While Proschan and Hunsberger (1995) confined the application of conditional power design to normally distributed observations, we consider more general and difficult settings in which the data are in the framework of continuous time and are subject to censoring. In particular, we derive a procedure appropriate for the analysis of the weighted log rank test under the assumption of a proportional hazards frailty model. The proposed method is illustrated through application to a brain tumor trial.Diagnosis of hydatidiform moles by polymorphic deletion probe fluorescence in Situ hybridization
AbstractChiang, S., Fazlollahi, L., Nguyen, A., Betensky, R., Roberts, D. J., & Iafrate, A. J. (n.d.).Publication year
2011Journal title
Journal of Molecular DiagnosticsVolume
13Issue
4Page(s)
406-415AbstractBecause products of conception often contain maternal and villous tissues, the determination of maternal and villous genotypes based on genetic polymorphisms can help discern maternal and paternal chromosomal contribution and aid in the diagnosis of hydatidiform moles. Polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes based on copy number variants are highly polymorphic and allow in situ determination of genetic identity. By using three informative PDPs on chromosomes 2p, 4q, and 8p, we compared maternal with villous genotypes and determined the ploidy of villous tissue. PDP FISH was performed on 13 complete moles, 13 partial moles, 13 nonmolar abortions, and an equivocal hydropic abortion. PDP FISH permitted definitive diagnosis of complete moles in five of 13 cases for which maternal and villous genotypes were mutually exclusive. A complete mole was highly suspected when all three PDP loci showed homozygous villous genotypes. The diagnosis of a complete mole by PDP FISH yielded a theoretical test sensitivity of 87.5%, specificity of 91.8%, an observed test sensitivity of 100%, and specificity of 92.3%. Triploidy was observed in all partial moles, in which diandric triploidy was confirmed in six cases. In the equivocal hydropic abortion, PDP FISH combined with p57 immunofluorescence revealed placental androgenetic/biparental mosaicism. PDP FISH can be used in clinical practice and research studies to subclassify hydatidiform moles and evaluate unusual products of conception.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.Diffusion imaging markers of accelerated aging of the lower cingulum in subjective cognitive decline
AbstractFlaherty, R., Sui, Y. V., Masurkar, A. V., Betensky, R., Rusinek, H., & Lazar, M. (n.d.).Publication year
2024Journal title
Frontiers in NeurologyVolume
15AbstractIntroduction: Alzheimer’s Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent. Methods: To better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available (N = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus. Results: SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD. Discussion: The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition.Digital quantification of precursor frequency in the fallopian tube and its significance
AbstractBijron, J. G., Ning, G., Laury, A. R., Quick, C. M., Betensky, R., Monte, N. M., King, E., McKeon, F. D., Xian, W., & Crum, C. P. (n.d.).Publication year
2012Journal title
Modern PathologyVolume
25Issue
12Page(s)
1654-1661AbstractA high frequency of precursor lesions is a risk factor for cancer in many organ systems but must be precisely quantified. Pelvic serous neoplasia is associated with an estimated increase in frequency of secretory cell outgrowths (SCOUTs) with loss of PAX2 protein (PAX2p) expression (PAX2p-null SCOUTs) in the fallopian tube. However, to confirm this, PAX2p-null SCOUTs must be precisely quantified relative to the epithelial surface. We developed a method by which fallopian tube sections were digitized using an iScan brightfield scanner (BioImagene) and uploaded in Adobe Photoshop CS3 Extended. Pixel length was translated into microns and epithelial length measured with the Magic Wand tool. SCOUTs were expressed as a function of total epithelial perimeter. Frequency, required perimeter length, topographic clustering tendency and effects of age were ascertained. SCOUT frequency per 10 cm was 0-4.60 for cases and 0-1.66 for controls, averaging 0.84 and 0.27, respectively, (P0.007). Required perimeter length for SCOUT detection was less in serous cancer cases and topographic distribution followed a random pattern without aberrant clustering. Age was also associated with SCOUT frequency (P0.025) and differences between cancers and controls were still significant after adjusting for age (P0.001). We describe an efficient method for quantifying epithelial perimeter in the fallopian tube and verify its relevance to precursor frequency. This has important implications for assessing precursor frequency both in the fallopian tube and in other organs - such as prostate, pancreas and colon - where epithelial precursors are integral to carcinogenesis.Displaying survival of patient groups defined by covariate paths : Extensions of the Kaplan-Meier estimator
AbstractJay, M., & Betensky, R. (n.d.).Publication year
2021Journal title
Statistics in MedicineVolume
40Issue
8Page(s)
2024-2036AbstractExtensions of the Kaplan-Meier estimator have been developed to illustrate the relationship between a time-varying covariate of interest and survival. In particular, Snapinn et al and Xu et al developed estimators to display survival for patients who always have a certain value of a time-varying covariate. These estimators properly handle time-varying covariates, but their clinical interpretation is limited. It is of greater clinical interest to display survival for patients whose covariates lie along certain defined paths. In this article, we propose extensions of Snapinn et al and Xu et al's estimators, providing crude and covariate-adjusted estimates of the survival function for patients defined by covariate paths. We also derive analytical variance estimators. We demonstrate the utility of these estimators with medical examples and a simulation study.DMBT1 polymorphisms : Relationship to malignant glioma tumorigenesis
AbstractSasaki, H., Betensky, R., Cairncross, J. G., & Louis, D. N. (n.d.).Publication year
2002Journal title
Cancer ResearchVolume
62Issue
6Page(s)
1790-1796AbstractThe deleted in malignant brain tumors 1 (DMBT1) gene on 10q25-26 is a candidate tumor suppressor gene in malignant gliomas, but its role is controversial, e.g., some DMBT1 homozygous deletions reflect unmasking of constitutional deletion polymorphisms by 10q loss. To clarify the role of DMBT1 in gliomagenesis, we investigated three reported deletion hot spots. Homozygous deletions at DMBT1 repeat 2-4 to 2-7 were found in 10 of 73 gliomas with 10q loss, but all 10 deletions reflected unmasking of constitutional hemizygous deletions. Alleles bearing deletion 2-4/2-7 were not selected significantly for by 10q loss, with retention of only 10 of 16 deleted alleles. No homozygous deletion was detected at locus 74k in the 5′ upstream region of DMBT1, and four tightly linked polymorphisms were found around this region; chromosome 10q loss randomly affected alleles with or without the variant sequences around locus 74k. Moreover, no significant selection pressure was detected for the haplotype with both deletion 2-4/2-7 and 5′ polymorphisms. There was no segregation of deletion 2-4/2-7 in glioma patients compared with unrelated individuals from reference families but a suggestion of a difference in the distribution of the 5′ polymorphisms between the reference individuals and glioma patients. Constitutional polymorphisms at DMBT1 repeat 2-9/2-10 appeared common in patients with both benign brain tumors and gliomas. A homozygote for both the 2-4/2-7 deletion and the 5′ polymorphisms had a glioma arise at a typical age and without an apparent family cancer predisposition. These data suggest that DMBT1 polymorphisms are not likely primary targets of 10q loss in malignant gliomas and do not support a major role for DMBT1 in gliomagenesis.Don't Be Blinded by the Blinding
AbstractBetensky, R., & Betensky, R. A. (n.d.).Publication year
2022Journal title
NEJM evidenceVolume
1Issue
3Page(s)
EVIDe2100063AbstractDon't Be Blinded by the BlindingBlinding of participants and investigators is universally accepted as a critical component of a high-quality randomized clinical trial. In conjunction with random assignment, blinding protects against several potential sources of bias, such as selection of participants, compliance and adherence to the protocol, differential dropout, researcher and patient assessments of outcomes, application of ancillary and supportive treatment, dose adjustments, encouragement by clinicians, and follow-up actions such as seeking and prescribing diagnostic testing. Unfortunately, complete blinding is simply not possible for some clinical trials, including those for many surgical interventions.Early Detection of Amyloid-Related Changes in Memory among Cognitively Unimpaired Older Adults with Daily Digital Testing
AbstractPapp, K. V., Jutten, R. J., Soberanes, D., Weizenbaum, E., Hsieh, S., Molinare, C., Buckley, R., Betensky, R., Marshall, G. A., Johnson, K. A., Rentz, D. M., Sperling, R., & Amariglio, R. E. (n.d.).Publication year
2023Journal title
Annals of NeurologyAbstractObjective: This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments. Methods: Thirty-six (21.9%) cognitively unimpaired older adults (aged 60–91 years) were classified with elevated β-amyloid (Aβ+) and 128 (78%) were Aβ− using positron emission tomography with 11CPittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years. Results: At the cross-section, there were no statistically significant differences in performance between Aβ+/− participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aβ+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aβ− participants (Cohen d = 0.49, 95% confidence interval = 0.10–0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001). Interpretation: Very early Aβ-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2023.Early Detection of Amyloid-Related Changes in Memory among Cognitively Unimpaired Older Adults with Daily Digital Testing
AbstractPapp, K. V., Jutten, R. J., Soberanes, D., Weizenbaum, E., Hsieh, S., Molinare, C., Buckley, R., Betensky, R., Marshall, G. A., Johnson, K. A., Rentz, D. M., Sperling, R., & Amariglio, R. E. (n.d.).Publication year
2023Journal title
Annals of NeurologyAbstractObjective: This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments. Methods: Thirty-six (21.9%) cognitively unimpaired older adults (aged 60–91 years) were classified with elevated β-amyloid (Aβ+) and 128 (78%) were Aβ− using positron emission tomography with 11CPittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years. Results: At the cross-section, there were no statistically significant differences in performance between Aβ+/− participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aβ+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aβ− participants (Cohen d = 0.49, 95% confidence interval = 0.10–0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001). Interpretation: Very early Aβ-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2023.Early Detection of Amyloid-Related Changes in Memory among Cognitively Unimpaired Older Adults with Daily Digital Testing
AbstractBetensky, R., Papp, K. V., Jutten, R. J., Soberanes, D., Weizenbaum, E., Hsieh, S., Molinare, C., Buckley, R., Betensky, R. A., Marshall, G. A., Johnson, K. A., Rentz, D. M., Sperling, R., & Amariglio, R. E. (n.d.).Publication year
2023Journal title
Annals of neurologyAbstractThis study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments.Early stopping to accept H(o) based on conditional power : Approximations and comparisons
AbstractBetensky, R. (n.d.).Publication year
1997Journal title
BiometricsVolume
53Issue
3Page(s)
794-806AbstractIt is intuitively appealing to clinicians to stop a trial early to accept the null hypothesis H0 if it appears that this will be the likely outcome at the planned end of the trial. We consider procedures that calculate at each time point the conditional probability of rejecting H0 at the end of the trial given the current data and some value of the parameter of interest. Lan, Simon, and Halperin (1982, Communications in Statistics C1, 207-219) calculate this probability under the design alternative, and Pepe and Anderson (1992, Applied Statistics 41, 181-190) use an alternative based solely on the current data. We investigate a modification to Pepe and Anderson's (1992) procedure that has a more satisfying interpretation. We define all of these procedures as formal sequential tests with lower stopping boundaries and study them in this context. This facilitates an improved understanding of the interplay of parameters by introducing visual displays, and it leads to an approximation for power by treating it as a boundary crossing probability. We use these tools to compare the performances of the different designs under a variety of parameter configurations.Effect of shipment, storage, anticoagulant, and cell separation on lymphocyte proliferation assays for human immunodeficiency virus-infected patients
AbstractWeinberg, A., Betensky, R., Zhang, L. I., & Ray, G. (n.d.).Publication year
1998Journal title
Clinical and Diagnostic Laboratory ImmunologyVolume
5Issue
6Page(s)
804-807AbstractLymphocyte proliferation assays (LPA), which can provide important information regarding the immune reconstitution of human immunodeficiency virus (HIV)-infected patients on highly active antiretroviral therapy, frequently involve shipment of specimens to central laboratories. In this study, we examine the effect of stimulant, anticoagulant, cell separation, storage, and transportation on LPA results. LPA responses of whole blood and separated peripheral blood mononuclear cells (PBMC) to different stimulants (cytomegalovirus, varicella-zoster virus, candida and tetanus toxoid antigens, and phytohemagglutinin) were measured using fresh specimens shipped overnight and frozen specimens collected in heparin, acid citrate dextrose (ACD), and citrate cell preparation tubes (CPT) from 12 HIV-infected patients and uninfected controls. Odds ratios for positive LPA responses were significantly higher in separated PBMC than in whole blood from ACD- and heparin-anticoagulated samples obtained from HIV-infected patients and from ACD-anticoagulated samples from uninfected controls. On separated PBMC, positive responses were significantly more frequent in fresh samples compared with overnight transportation for all antigens and compared with cryopreservation for the candida and tetanus antigens. In addition, viral antigen LPA responses were better preserved in frozen PBMC compared with specimens shipped overnight. CPT tubes yielded significantly more positive LPA results for all antigens, irrespective of the HIV patient status compared with ACD, but only for the candida and tetanus antigens and only in HIV- negative controls compared with heparin. Although HIV-infected patients had a significantly lower number of positive antigen-driven LPA responses compared with uninfected controls, most of the specimen processing variables had similar effects on HIV-positive and -negative samples. We conclude that LPA should be performed on site, whenever feasible, by using separated PBMC from fresh blood samples collected in either heparin or ACD. However, if on-site testing is not available, optimal transportation conditions should he established for specific antigens.Effects of unmeasured heterogeneity in the linear transformation model for censored data
AbstractZhang, B., Li, Y., & Betensky, R. (n.d.).Publication year
2006Journal title
Lifetime Data AnalysisVolume
12Issue
2Page(s)
191-203AbstractWe investigate the effect of unobserved heterogeneity in the context of the linear transformation model for censored survival data in the clinical trials setting. The unobserved heterogeneity is represented by a frailty term, with unknown distribution, in the linear transformation model. The bias of the estimate under the assumption of no unobserved heterogeneity when it truly is present is obtained. We also derive the asymptotic relative efficiency of the estimate of treatment effect under the incorrect assumption of no unobserved heterogeneity. Additionally we investigate the loss of power for clinical trials that are designed assuming the model without frailty when, in fact, the model with frailty is true. Numerical studies under a proportional odds model show that the loss of efficiency and the loss of power can be substantial when the heterogeneity, as embodied by a frailty, is ignored.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.Post hoc selection of a method for multiplicity adjustment of secondary and exploratory endpoints
AbstractVu, P., & Betensky, R. (n.d.).Abstract~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., 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.Erratum : Effects of unmeasured heterogeneity in the linear transformation model for censored data (Lifetime Data Analysis (2007) DOI:10.1007/s10985-006- 9008-y)
AbstractZhang, B., Li, Y., & Betensky, R. (n.d.).Publication year
2007Journal title
Lifetime Data AnalysisVolume
13Issue
3Page(s)
431Abstract~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.